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These authors elucidate the most important aspects of genetic background, neuropeptide secretion and action, neuronal pathways, adipokines, gut hormones, and environmental influences physical activity, pharmacologic agents, and surgical alteration of the gastrointestinal tract , as well as the complex interactions among them.

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Texto original. By contrast, mice with a muscle-specific deletion of HDAC3 are insulin resistant, yet have greater endurance and resistance to muscle fatigue than wild-type mice, as the HDAC3-deficient muscle undergoes a fuel source switch favoring protein catabolism and lipid oxidation over glucose utilization Hong et al.

In addition to modulating histone acetylation such as H3K27ac and H3K9ac, HDAC3 also forms complexes with many transcriptional regulators such as REV-ERBa, NCoR, ERRα, and PGC-1α, which may contribute to the different roles of HDAC3 in regulating substrate metabolism in different metabolic organs Emmett and Lazar, Although inhibitors of class II HDACs do not show metabolic phenotype Galmozzi et al.

For example, overexpression of HDAC4 in adipocytes leads to beige adipocyte expansion and reduced adiposity PauLo et al. Global knockout of HDAC5 mice exhibit increased food intake and obesity when fed HFD due to the enhanced STAT3 acetylation, which impairs the leptin signaling in hypothalamus Kabra et al.

Interestingly, HDAC5 knockout animals demonstrate normal glucose and insulin tolerance despite elevated body adiposity and increased hepatic fat deposition owing to H3K9ac-mediated interleukin-6 production in the muscle Kabra et al.

Finally, HDAC9 knockout mice show upregulated expression of beige adipocyte marker genes, particularly during an HFD, in association with increased energy expenditure and adaptive thermogenesis Chatterjee et al.

Protein levels of class IIb HDACs HDAC6 and HDAC10 are markedly reduced in both WAT and BAT of HFD-fed obese mice Qian et al. Mice with an adipose-specific depletion of HDAC6 display increased fat storage due to enhanced acetylation of cell death-inducing DFFA-like effector C CIDEC Qian et al.

HDAC6 may also affect energy metabolism by altering intestinal microbiota. Feeding HDAC6-deficient mice with HFD causes depletion in representatives of the S family and Lactobacillus but enrichment with Bacteroides and Parabacteroides , changes of which contribute to the development of obesity Lieber et al.

HDAC11 is the only member of class IV HDAC. HDAC11 deletion enhances brown and beige fat activity, leading to enhanced energy expenditure and leanness Bagchi et al.

HDAC11 is also highly expressed in the skeleton muscle. HDAC11 deficiency induces a glycolytic to oxidative muscle fiber switch in vivo , providing a mechanistic explanation for the improved muscle strength and fatigue resistance Hurtado et al.

Overall, extensive studies of HATs and HDACs have emphasized the crucial role of histone acetylation and deacetylation in bridging epigenetic, transcriptional, and signaling phenomena to metabolism in obesity Figure 2.

Interestingly, it does not appear to have a clear pattern for the different classes of HDACs in regulating energy metabolism Table 1. Substrate specificity, tissue distribution, and interacting partners may determine their roles in regulating energy metabolism.

The selectivity, on the other hand, may provide an opportunity to identify inhibitors and activators of HDACs for treatment of obesity. Modifiers for histone acetylation and methylation. Histone acetylation and deacetylation are catalyzed by HATs and HDACs, respectively.

Extensive studies of HATs and HDACs have emphasized the crucial role of histone acetylation and deacetylation in bridging epigenetic, transcriptional, and signaling phenomena to metabolism in obesity. Histone methylations are dynamically regulated by HMTs and HDMs. Histone methylation occurs on basic residues lysine and arginine and confers active or inhibitory transcription, depending on their location and methylation status.

Red color indicates the modifiers participated in energy metabolism. Histone methylation occurs on basic residues lysine and arginine that can be mono- me1 , di- me2 , or tri-methylated me3 on their ɛ-amine group. Different from histone acetylation, which is associated with active chromatin states, histone methylations may confer either active or repressive transcription depending on their positions and methylation states Figure 2.

For example, H3K4, H3K36, and H3K79 methylations are markers of active transcription, whereas H3K9, H3K27, and H4K20 methylations are associated with suppressive transcription.

HMTs, except the H3K79 methyltransferase DOT1, contain a defined SET-domain with an intrinsic histone lysine-specific methyltransferase activity. Most methyltransferases show a strong preference for specific sites.

Histone methylation was considered stable until the report of lysine-specific demethylase 1 LSD1 in Shi et al. Subsequently, 18 HDMs containing Jumonji domain with selective substrate specificity were identified Han et al. It is important to note that one specific lysine residue of histone protein may be modulated by multiple HMTs and HDMs.

The dynamics of histone methylation regulated by HMTs and HDMs provide innovative tools to reprogram histone methylation and gene expression profiles.

Several HMT and HDM inhibitors are currently in clinical trials for cancer treatment Cheng et al. Multiple HMTs and HDMs have also been shown to regulate energy metabolism.

Interestingly, however, MLL4 heterozygous mice exhibit low body fat mass, improved hepatic steatosis, enhanced glucose tolerance, and insulin sensitivity.

MLL4-regulated PPARγ2 activity and bile acids are thought to be involved in the metabolic phenotype in the MLL4 heterozygous mice Kim et al. LSD1 is the first identified HDM that selectively demethylates H3K4me1 and H3K4me2 through a flavin adenosine dinucleotide FAD -dependent oxidative reaction Shi et al.

LSD1 may also act on mono- and di-methylated H3K9. Several lines of adipose LSD1 knockout mice have been reported. It appears that LSD1 is essential for brown and beige fat development via regulating H3K4 and H3K9 methylation as well as interacting with transcription factors such as PRDM16 and zinc finger protein ZFP Duteil et al.

Notable among the histone methylation modifiers, dynamics of H3K9 methylation have been highly related to energy metabolism. The methyltransferases that methylate H3K9 include euchromatic histone—lysine N-methyltransferase 1 EHMT1, also known as G9a-like protein, GLP , EHMT2 also known as G9a , SETDB1, PRDM2, SUV39H1, and SUV39H2 Krishnan et al.

EHMT1 may form a complex with PRDM16 to control brown adipose cell fate by depositing the suppressive H3K9me2 and H3K9me3, leading to muscle-selective gene suppression and brown fat gene activation Ohno et al. Adipose-specific deletion of EHMT1 leads to a marked reduction of BAT-mediated adaptive thermogenesis, obesity, and systemic insulin resistance Ohno et al.

EHMT2 is functionally related to EHMT1. EHMT2 knockout driven by aP2-Cre also increases adiposity with elevated insulin and leptin levels, although the mechanism is thought to be EHMT2-mediated adipogenesis Wang et al. On the other hand, recently reported muscle EHMT2 knockout female mice are resistant to HFD-induced obesity and hepatic steatosis Zhang et al.

The liver deletion of EHMT2 results in aggravated lipopolysaccharide-induced peroxidation and proinflammatory response Lu et al. Therefore, H3K9 methyltransferases regulate energy metabolism and adiposity in different metabolic organs in the context-dependent fashion.

The H3K9 demethylase Jumonji domain-containing protein 1A JMJD1A, also known as JHDM2A or KDM3A is induced after β-adrenergic stimulation. JMJD1A regulates adipose thermogenesis through two mechanisms. Under acute stimulation, JMJD1A is phosphorylated by protein kinase A, which facilitates long-range chromatin interactions and target gene activation.

Interestingly, this is independent of H3K9 methylation Abe et al. Under chronic adrenergic stimulation, JMJD1A erases the suppressive H3K9me2 modification on beige-selective gene promoters in iWAT to maintain sustained activation of thermogenic genes in response to chronic cold exposure Abe et al.

JMJD1A deficiency results in obesity due to reduced thermogenesis Tateishi et al. Methylation of H3K27 marks suppressive gene transcription.

Enhancer of zeste homolog 2 EZH2 , the functional enzymatic component of the PRC2, promotes H3K27me3, while JMJD3 also known as KDM6B and ubiquitously transcribed X-chromosome tetratricopeptide repeat protein UTX specifically demethylate H3K Adipocyte-specific EZH2 knockout mice, generated by crossing EZH2-floxed mice to adiponectin-Cre mice, display significantly increased body weight, adipose tissue mass, and adipocyte cell size, without changes in glucose or insulin tolerance.

The increased adiposity is not caused by altered energy expenditure but by increased ApoE-mediated lipid uptake in adipocytes Yiew et al. JMJD3 demethylates suppressive H3K27me3 to activate BAT-selective genes and promote development of beige adipocytes Pan et al. JMJD3 may also form a complex with SIRT1 and regulates fatty acid oxidation in the liver Seok et al.

Similarly, UTX demethylase positively regulates brown adipocyte thermogenic program through coordinated control of demethylating H3K27me3 and acetylating H3K27, switching the transcriptional repressive state to the transcriptional active state at the promoters of PRDM16, UCP1, and PGC-1α.

UTX deficiency in brown fat promotes HFD-induced obesity Zha et al. Therefore, demethylation of suppressive H3K27me3 in metabolic organs generally causes increased energy metabolism.

Methylation of suppressive H4K20 is catalyzed by three distinct lysine methyltransferase enzymes, KMT5a also known as SETD8, SET8, and PR-Set7 , KMT5b SUVH1 , and KMT5c SUVH2. Double knockout of Kmt5B and Kmt5C in early mesenchymal precursor cells using Myf5-Cre increases BAT metabolic activity and enhances browning of WAT, ultimately counteracting DIO Pedrotti et al.

Activation of PPARγ is reported to be the underlying mechanism for the improved metabolic phenotype in the Kmt5B and Kmt5C double-knockout mice Pedrotti et al.

Interestingly, however, a more recent study shows that KMT5c but not KMT5a or KMT5b is essential for thermogenic gene expression in fat cells Zhao et al. Mice with adipose-specific Kmt5c knockout driven by Adipoq-Cre exhibit reduced adipose thermogenesis and are susceptible to obesity when fed a HFD.

Mechanistically, the increased p53 expression from removal of suppressive H3K20me3 in the p53 promoter with Kmt5c knockout is involved in the activation of thermogenic genes Zhao et al. Different Cre lines Myf5 vs.

adiponectin that delete Kmt5c at different stages of adipocyte differentiation may contribute to the discrepancy of the roles of Kmt5c in regulating adipose thermogenesis. It is worth noting that histone methylation and acetylation are dynamically interactive.

The enhancers with H3K4me1 have been shown to serve a priming role during development and in response to environmental cues Ghisletti et al. In warm beige adipocytes, H3K4me1 signals are increased in the enhancer regions of thermogenetic genes such as UCP1 and CPT1B, indicating that warm beige adipocytes retain an epigenomic memory from prior cold exposure at a small, but key, subset of cis -elements Roh et al.

In addition to the extensively studied acetylation and methylation, histone proteins are subjected to other post-translational modifications such as phosphorylation, succinylation, malonylation, sumoylation, ADP-ribosylation, O-GlcNAcylation, and lactylation. Quantitative proteomic analysis using the mass spectrometry-based label-free and chemical stable isotope labeling has identified histone marks in the liver of HFD-induced obese mice Nie et al.

Some of these modifications may be involved in adipocyte function. For example, ADP-ribosylation of glutamate Glu35 and the subsequent reduction of H2B-Ser36 phosphorylation inhibit adipocyte differentiation Huang et al.

H2B O-GlcNAcylation at Ser may be involved in brown adipogenesis Cao et al. Overall, the roles of these histone modifications in regulating energy metabolism remain to be elucidated.

More than types of RNA modifications have been identified and N 6 -methyladenine m 6 A is the most abundant internal modification in messenger RNA mRNA and ncRNA Wei et al. BAT-specific METTL3 knockout mice show reduced energy expenditure and are predisposed to HFD-induced obesity and metabolic syndrome.

Mechanistically, deletion of METTL3 decreases m 6 A modification and the expression of BAT-specific mRNA, including PRDM16, PPARγ, and UCP1 Pan et al. On the other hand, WTAP heterozygous knockout mice are protected from DIO with elevated energy metabolism and improved insulin sensitivity.

WTAP knockdown induces cell cycle arrest and impairs adipogenesis by suppressing cyclin A2 during mitotic clonal expansion Kobayashi et al. Future studies of tissue-specific knockout of WTAP will be necessary to distinguish the developmental effects vs.

direct effects of m 6 A modification on metabolic gene expression. FTO is the first identified m 6 A demethylase on mRNA Jia et al. In the large-scale GWAS studies, variants in the FTO gene are strongly associated with BMI and obesity, suggesting an important role of FTO in energy metabolism Dina et al.

Interestingly, a CpG site in the first intron of the FTO gene shows hypomethylation, suggesting FTO per se can also undergo epigenetic regulation Toperoff et al.

Ubiquitous overexpression of FTO leads to a marked increase in food intake, body weight, and fat accumulation in mice, while whole-body knockout of FTO reduces adiposity and DIO accompanied with increased energy expenditure and systemic sympathetic activation Fischer et al.

FTO is highly expressed in hypothalamus Gerken et al. Mice with brain-specific deletion of FTO display significantly higher metabolic rates and reduced body weight Gao et al. FTO is also expressed in peripheral metabolic organs including the adipose tissue, liver, and skeletal muscle Gerken et al.

In human WAT, FTO expression is inversely correlated with BMI Kloting et al. FTO-deficient mice exhibit an increase of UCP1 expression in WAT, indicating browning of WAT Tews et al. By contrast, hepatocyte-specific FTO depletion fails to affect body weight, fat mass, glucose metabolism, and key parameters of energy expenditure, indicating the dispensable role of hepatic FTO for the control of energy homeostasis Mittenbuhler et al.

Treatment of obese mice with entacapone improves body weight regulation and glucose tolerance and increases adipose thermogenesis owing to decreased FTO-catalyzed m 6 A demethylation of FOXO1 mRNA Peng et al. Expression of FTO is also upregulated in the skeletal muscle of obese mice and therefore demethylates the methylated mRNA by removing m 6 A Wu et al.

However, FTO appears to be essential to skeletal muscle development WaNg et al. Another m 6 A demethylases ALKBH5 can be activated by hypoxia resulting in decreased m 6 A level of mRNA Wang et al. Activation of ALKBH5 in hypoxia is crucial for the adaption to hypoxia for efficient energy generation, since silencing ALKBH5 blocks cellular ATP production Wang et al.

The effects of ALKBH5 on systemic energy metabolism in obesity remain to be elucidated. NcRNAs including microRNAs miRNAs , long noncoding RNAs lncRNAs , and circular RNAs circRNAs are emerged to be important epigenetic regulators in many physiological processes, including energy metabolism Marchese et al.

Omics approaches have identified a variety of differentially expressed miRNAs in metabolic organs in obesity, and some of them are functional in regulating energy metabolism Dumortier et al. miRNAs may also be secreted from metabolic organs and serve as endocrine factors to regulate systemic energy expenditure Ji and Guo, Notably, adipose tissue-specific knockout of the miRNA-processing enzyme Dicer exhibits a substantial decrease in circulating exosomal miRNAs, leading to increased FGF21 expression in the liver Thomou et al.

LncRNAs are conventionally defined as a transcript longer than nucleotides in length lacking protein-coding capability Kung et al. Accumulating evidence suggests that lncRNAs play important functional roles in modulating the transcription and translation of energy metabolism-related genes Tan et al.

Several BAT- and WAT-specific lncRNAs have been identified via de novo reconstruction of transcriptomes or meta-analysis of published datasets Alvarez-Dominguez et al. For example, comprehensive transcriptome study by RNA sequencing in adipocytes isolated from interscapular BAT, iWAT, and eWAT in DIO mice revealed a set of obesity-dysregulated lncRNAs.

The most prominent lncRNAs is lnc-Lep, which is transcribed from an enhancer region upstream of leptin Lo et al. Functional studies indicate that lnc-Lep is essential for adipogenesis and required for the maintenance of adipose leptin expression.

DIO mice lacking lnc-Lep show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment. Importantly, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms in the region of human lnc-Lep with lower plasma leptin levels and obesity Dallner et al.

Moreover, these two lncBATEs are also required for browning of iWAT Alvarez-Dominguez et al. Another important lncRNA involved in energy metabolism is encoded by the maternally imprinted gene H H19 is upregulated in BAT under cold exposure and decreased in BAT of DIO mice Schmidt et al.

Ubiquitous overexpression of H19 enhances BAT thermogenesis, increases energy expenditure, and prevents DIO, whereas fat H19 loss sensitizes toward HFD weight gains. Mechanistically, lncRNA H19 forms a complex with the DNA methyltransferase MBD1 and recruits suppressive H3K9me3 to maintain quiescence of obesity-predisposing paternally expressed genes in BAT Schmidt et al.

Finally, recent studies also suggest that lncRNAs can act as competitive endogenous RNA ceRNA by binding to miRNAs, hence inhibiting miRNA activity and regulating mRNA expression Salmena et al. However, the precise roles of the ceRNA—miRNA network in regulating energy metabolism need to be further studied.

CircRNAs are covalently closed single-stranded RNA rings generated from a process known as back-splicing or head-to-tail circle splicing, which involves joining of a splice donor to an upstream splice acceptor of precursor mRNA. Emerging evidence suggests that circRNAs may play an important role in regulating adipose function and energy metabolism.

Differentially expressed circRNAs in the adipose tissue from obese and lean subjects have been reported using circRNA microarrays. Among these, circSAMD4A can act as a miRNA sponge by interacting with miRp. Knockdown of circSAMD4A inhibits adipocyte differentiation Liu et al. Several other circRNAs such as ciRS circRNA sponge for miR and circNrxn2 miR sponge may promote WAT browning Zhang et al.

Not all circRNAs regulate adipose function through miRNA sponges. Deep sequencing of visceral and subcutaneous fat identifies thousands of adipose circRNAs, many of which are dynamically regulated during adipogenesis and obesity.

Among the regulated circRNAs, circArhgap is required for adipogenesis, not through sponging miRNAs Arcinas et al. The understanding of circRNA biology is at a very early stage.

CircRNAs are stable compared to linear RNAs. Future studies focusing on their roles in energy metabolism may help provide novel therapeutic strategy for treating obesity. The activity of epigenetic factors is regulated at multiple levels including transcription, translation, and post-translational modifications.

These metabolites are therefore regarded as metabolic sensors for programing pathway network of energy metabolism Etchegaray and Mostoslavsky, ; Yang et al.

Metabolites as cofactors of the epigenetic machinery. These metabolites are therefore regarded as metabolic sensors for programing pathway network of energy metabolism. Metabolic cofactors are produced in respective metabolic pathways, which participate in epigenetic modification processes through enzymes.

Epigenetic modifications can be assessed by detecting relevant metabolic cofactors, which can be interfered with by targeting the regulation of metabolic cofactor expression. SAM is the universal methyl donor to both DNMT and HMT enzymes. SAM is synthesized from the condensation of methionine and ATP via methionine adenosyltransferase.

A positive correlation between SAM levels, BMI, and adiposity mass has been reported Elshorbagy et al. Tissue SAM levels are therefore modulated by the availability of methionine, an essential amino acid in one-carbon metabolism.

Methionine restriction rapidly reduces adiposity and improves insulin sensitivity and fatty liver in mice Malloy et al. Although the underlying mechanisms for the beneficial metabolic effects of methionine deficiency remain to be fully elucidated, methionine deficiency drastically reduces liver SAM levels and H3K4 trimethylation Mentch et al.

In adipose tissue, SAM-regulated histone methylation may have a positive effect on systemic energy metabolism. Nicotinamide N-methyltransferase NNMT , which is highly expressed in adipose tissue, catalyzes the methylation of nicotinamide using SAM as a methyl donor.

NNMT knockdown in adipose tissue elevates SAM levels and increases H3K4 methylation, which in turn enhances the key enzymes in the polyamine flux to increase systemic energy metabolism Kraus et al.

The one-carbon metabolism and SAM production may also affect DNA methylation reprograming during mammalian development, in which genomes of germ cells and embryo undergo two waves of global demethylation and remethylation Li et al.

It has been shown that maternal one-carbon metabolism may affect the offspring energy metabolism and development of obesity, although the underlying mechanisms remain elusive Mabasa et al. α-KG is an intermediate metabolite generated in the tricarboxylic acid cycle from isocitrate dehydrogenase IDH -mediated isocitrate conversion.

α-KG can also be replenished from glutamine anaplerosis. In addition to its roles as a metabolic substrate in the cytosol and mitochondria, α-KG can also enter the nucleus and serves as a cofactor for TET-mediated DNA demethylation and JHDM family HDM activity to modify epigenetic marks Teperino et al.

During early brown adipogenesis, the cellular α-KG levels are profoundly increased and required for active DNA demethylation of the PRDM16 promoter Yang et al.

A recent study also shows that IDH1-mediated α-KG modulates trimethylation of H3K4 in the promoters of genes associated with brown adipogenesis Kang et al.

Furthermore, knockdown of SIRT5 reduces intracellular α-KG concentration, leading to elevated suppressive H3K9me2 and H3K9me3 abundance at promoter regions of PPARγ and PRDM16 in adipocytes Shuai et al. Finally, dietary α-KG supplement has been shown to promote beige adipogenesis and prevent obesity in middle-aged mice Tian et al.

These results provide strong evidence that α-KG can be an attractive therapeutic agent for obesity treatment by modulating epigenetic factor activity in brown and beige adipocytes.

Acetyl-CoA is a central metabolite positioned at the crossroads of carbohydrate, fat acid, and amino acid metabolism. Acetyl-CoA is also a substrate for protein acetylation including HATs Pietrocola et al. In yeast, stem cells, and cancer cells, HATs can be regulated by the availability of acetyl-CoA, leading to global acetylation changes of histone protein.

Acetyl-CoA levels have been reported to be altered in the adipose tissue and liver Dharuri et al. However, it is challenging to determine whether the altered acetyl-CoA regulates histone acetylation and gene expression, because acetyl-CoA is modulated by multiple inputs, outputs, and inter-organ crosstalk Yang et al.

Sirtuin deacetylases Sirt1, Sirt6, and Sirt7 are predominantly located in the nucleus, among which Sirt1 plays a major role in regulating mitochondrial function, mainly by modulating the acetylation of PGC-1α, the master regulator of mitochondrial biogenesis and function.

Sirt1 may also modify histone acetylation such as H3K9ac and H4K16ac to regulate target gene expression Canto et al. SIRT6 may deacetylate H3K9ac and SIRT6 overexpression increases male longevity with gene regulation in a similar way as mice following a caloric restriction diet Kanfi et al.

SIRT7-mediated deacetylation of H3K18ac may epigenetically facilitate the effects of SIRT7 on regulating glucose and lipid metabolism Shin et al. Epigenetic modifications are highly dynamic in response to environmental factors such as diet and exercise.

Although most studies are correlational, several intervention studies have also been performed to dissect the impact of lifestyle modifications on the human epigenome in obesity.

Different dietary patterns, nutrients, and food components have been related to epigenetic processes that may contribute to the susceptibility of obesity Ideraabdullah and Zeisel, ; Castellano-Castillo et al. In the pioneer studies of Dutch famine during the — winter at the end of World War II, individuals exposed to famine during gestation develop metabolic syndrome including obesity and hypercholesterolemia in adulthood de Rooij et al.

Similar studies of the Chinese Great Famine — show that early-life exposure to severe famine is associated with excessive risk of dyslipidemia WaNg et al. A genome-wide exploration of CpG methylation of whole-blood DNA identifies six CpGs that are associated with BMI and triglycerides.

As one-carbon metabolism depends on the dietary methyl donors, DNA methylation can be influenced by choline, methionine, betaine, and folate Ducker and Rabinowitz, Maternal intake of these methyl-group donors in the periconception period is associated with DNA methylation in genes related to growth insulin like growth factor 2, IGF2 , metabolism retinoid X receptor-α, RXRA , and appetite control leptin Pauwels et al.

Interestingly, prenatal overnutrition and an obese maternal environment are also associated with DNA methylation changes in genes related to metabolic diseases in the offspring Liu et al. Both saturated fatty acids or polyunsaturated fatty acids overfeeding could increase the global degree of DNA methylation in adipose tissue of young, healthy adults in parallel with their body weight increase Perfilyev et al.

Therefore, dietary factors may alter the epigenome especially DNA methylation, although the causative roles in the pathogenesis of obesity deserve further investigation. Dietary supplements such as resveratrol, nicotinamide riboside, and curcumin have been shown to improve energy metabolism partially through epigenetic mechanisms.

Resveratrol has received great attentions because it is a component of plant-based foods especially red wine. Resveratrol may activate SIRT1 and modify histone protein Fernandes et al. Although the beneficial effects of resveratrol on metabolism are convincing in cell culture and animal studies, human clinical trials have yielded mixed results Bitterman and Chung, Consistently, nicotinamide riboside is effective in reducing obesity and glucose levels in animals.

However, large clinical trials are required to determine whether nicotinamide riboside is effective in treating metabolic diseases in humans. Finally, intake of curcumin, a polyphenolic compound in turmeric, is correlated with reduced BMI and body weight in patients with metabolic syndrome Akbari et al.

Physical activity and exercise may alter epigenetic signatures, especially DNA methylation as described in a recent systemic review Barron-Cabrera et al.

Excise increases muscle mitochondrial contents partially due to increased PGC-1α expression. Both acute and chronic exercises have been shown to reduce promoter PGC-1α methylation Barres et al.

Since PGC-1α and HDAC4 are established to play important roles in energy metabolism, altered DNA methylation of these genes may contribute to the beneficial metabolic effects of physical activity and exercise.

The dynamics of the histone, DNA, or RNA modifications provide an opportunity to alter epigenetic factor activity for obesity treatment.

Both DNMT and HDAC inhibitors are emerging treatments for cancer. Some of the inhibitors have been tested in animals for potential obesity and diabetes treatment.

Inhibition of DNA methylation by 5-azacytidine at early stage of differentiation suppresses adipogenesis, while inhibition of DNA methylation at late stage of differentiation promotes lipogenesis and adipocyte phenotype Yang et al.

Sodium butyrate, an HDAC pan-inhibitor, has been shown to alleviate HFD-induced obesity Gao et al. A subsequent study shows that class I but not class II HDAC inhibitors enhance whole-body energy expenditure through increased mitochondrial biogenesis in the skeletal muscle and adipose tissues Galmozzi et al.

Interestingly, however, the class IIa HDAC inhibitor Scriptaid is shown to increase energy expenditure without altering body weight due to increased food intake. Scriptaid enhances skeletal muscle insulin action and cardiac function in obese mice Gaur et al.

Administration of the HDAC3 inhibitor HD may also improve insulin sensitivity via upregulating PPARγ acetylation in a mouse model of HFD-induced obesity Jiang et al. Targeting specific miRNAs that regulate energy metabolism using gain- and loss-of-function tools such as miRNA mimics, antagonists, and inhibitors may potentially be a strategy for obesity treatment.

However, the major obstacle is side effects and toxicity. For example, miRa knockout mice are susceptible to DIO Lavery et al. MRX34, a liposomal miRa mimic initially developed for treating hepatocellular carcinoma and hematological malignancies, might have beneficial effects on obesity.

However, MRX34 caused severe immune-mediated adverse effects leading to early termination of the phase I clinical trial for cancer treatment Beg et al. miR, the most abundant miRNA in the liver, promotes hepatic lipogenesis Long et al.

Miravirsen is an antisense oligonucleotide drug inhibiting miR for hepatitis C treatment Israelow et al. Miravirsen has also been shown to improve liver steatosis and reduce cholesterol levels Esau et al. Rapid development in epigenomic technology and the increasing body of epigenomic data offer unprecedented opportunities to delineate how the interplay between genetic, environmental, and epigenetic components regulates energy metabolism in obesity and T2DM.

Signatures of epigenetic markers including DNA methylation, histone modification, and ncRNAs are found to be associated with obesity. There is also substantial evidence demonstrating that epigenetic mechanisms play causal roles in the development of obesity and T2DM.

Identification of metabolites as regulators of epigenetic factors such as HATs, HMTs, and sirtuins makes it possible to design small-molecule drugs to modulate epigenetic factor activity for obesity and T2DM treatment.

The advancement of our understanding in epigenetic regulation of energy metabolism also represents several challenges. Many epigenetic regulators are important for development.

It is less clear from studies using knockout mouse models whether the effects of the epigenetic factors on energy metabolism are developmental or physiological.

Studying knockout in adult mice using inducible cre recombinase will avoid secondary effects of development and provide significant insights into the physiological roles of epigenetic factors in regulating energy metabolism.

Additionally, the epigenetic factors such as HATs and HMTs often form large regulatory complexes. For drug development, it is important to understand whether the effects of histone modifiers on energy metabolism are caused by altered enzyme activity or disruption of the regulatory complexes.

Furthermore, epigenetic factors regulate a broad spectrum of target genes, often in a tissue-specific manner. Understanding the mechanisms by which epigenetic factors regulate metabolic gene expression is essential to selectively target the epigenetic machinery for obesity treatment while avoiding adverse effects.

Finally, studies need to elucidate how life styles such as diet and exercise alter epigenetic factor activity and how the altered epigenetic factors regulate energy metabolism at the molecular, cellular, organ, and whole-body levels. It is also key to determine which observations in animal models can be translated to humans.

Despite these challenges, ultimately, in the postgenomic era, the integration of genomic and epigenomic landscapes will not only deepen our understandings of molecular mechanisms for energy metabolism, but may also lead to the identification of novel strategies for treating obesity and T2DM.

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Article Open access 02 October A Biopsychosocial Model of Social Media Use and Body Image Concerns, Disordered Eating, and Muscle-Building Behaviors among Adolescent Girls and Boys Article 06 January Use our pre-submission checklist Avoid common mistakes on your manuscript. Footnote 3 Between the s and the s, the genetics of obesity was extensively investigated in humans through family and twin studies, which estimated that the heritability of traits like BMI, WC, and WHR ranges between 0.

Footnote 4 Since the late s, with technological and methodological advancements, researchers started to seek specific alleles associated with obesity.

Footnote 6 Early GWAS allowed researchers to identify some new potential candidate genes operating both through adipose tissue and through the central nervous system and affecting appetite, satiety, energy expenditure, and feeding behavior Herrera and Lindgren ; Locke et al.

Footnote 8 Some scholars have suggested that part of the problem might also depend on how obesity is operationalized. Footnote 10 To clarify this point, we need to introduce the distinction between characters and character states. My Mother, Obesity and Me: Our Narrative.

How Obesity Is Intimately Related to Biopsychosocial and Spiritual Factors Chapter © Recent Developments in the Epidemiology of Obesity Chapter © Childhood Obesity: What Harm, Any Solutions?

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However, the precise role of adipokines in acute and chronic pancreatitis, as well as in pancreatic cancer, is unclear yet and needs to be further investigated.

Controversial results regarding the functions of leptin, visfatin, adiponectin, and resistin have been found. In summary, obesity-linked type-2 diabetes is characterized by the decreased number and function of pancreatic β-cells.

The impairment in β-cell function, as well as the number of β-cells, has been related to lipotoxicity with the concomitant increased oxidative and endoplasmic reticulum stress and the adipokine-induced inflammation processes Halban et al.

Obesity has been involved as a risk factor at different stages of liver disease Manne and Saab, , not only causing non-alcoholic fatty liver disease NAFLD but also impairing the general state of patients with other preexisting conditions such as viral hepatitis.

However, fat deposition is not the only observation of NAFLD, an inflammatory process coexists, with hepatocellular ballooning injury that can lead to fibrosis and cirrhosis Brunt et al.

Since triglycerides have been shown to accumulate in the liver through different manners, there is not a unique mechanism by which obesity could lead to NAFLD. Moreover, beyond the role of triglycerides, insulin resistance does have an important role in the development of fatty liver Marchesini et al.

Free fatty acid uptake by the liver not only leads to hepatic steatosis but also produces hepatic toxicity by oxidative stress-dependent mechanisms Manne and Saab, In this connection, it is thought that hepatic accumulation of triglycerides occurs first hepatic steatosis or fatty liver and then, since fatty liver is more prone to suffer oxidative injury, it evolves to steatohepatitis Qureshi and Abrams, The link between obesity and NAFLD has been explained by different hypotheses which take into consideration the portal hypothesis, the endocrine role of adipokines, and many observations from lipodystrophic states.

It has been mentioned that visceral adipocytes constitute an important source of fatty acids and other factors entering the portal circulation Qureshi and Abrams, The portal hypothesis supports the idea that the increased hepatic uptake of fatty acids coming from an enlarged visceral adipose tissue leads to decreased hepatic insulin clearance and thus increased circulating insulin.

Indeed, fatty acids stimulate hepatic gluconeogenesis, triglyceride synthesis, and hepatic glucose output by altering insulin signaling Kahn and Flier, On the other hand, adipokines are also involved in the development of NAFLD during obesity.

For example, in addition to all the general effects of leptin, this adipokine has been shown to better liver enzymes and hepatic fat content, thus attenuating different manifestations of fatty liver in patients with lipoatrophy and metabolic syndrome Lee et al.

In obese NAFLD patients, leptin levels correlate with the severity of fatty liver, thus suggesting the presence of leptin resistance, probably due to a failure in leptin signaling.

Low levels of adiponectin have been found in NAFLD patients, probably due to the concomitant high levels of IL-6 and TNFα found, both of which inhibit adiponectin expression. Therapy with adiponectin administration has shown to improve insulin resistance in animal models of obesity; however, in lipodystrophic animal cases, the complete reversal of insulin resistance requires the co-administration of leptin.

Adipose tissue-derived TNFα and IL-6 cause the activation of Kupffer cells which leads to hepatic fibrogenesis. Moreover, TNFα has been shown to be also produced by the Kupffer cells, playing a key role in the pathogenesis of NAFLD Qureshi and Abrams, Additionally, fatty liver, accompanied by insulin resistance and diabetes, is usually observed in lipodystrophic patients, where the fatty liver usually progresses to cirrhosis.

Among different explanations proposed, reduced adiponectin and leptin levels are thought to be responsible for the presence of NAFLD in lipodystrophic individuals.

Not only has obesity been related to the development and progression of NAFLD, but also with the impairment of other hepatic conditions, being obesity considered as a strong risk factor for different liver cancers.

Very interestingly, the mere losing weight of obese patients has been shown to be sufficient not only to improve the results of several hepatic treatments Nobili et al. As a general picture, obesity is linked to functional limitations in muscle performance and increased probability of developing a functional disability related to strength, mobility, postural, and dynamic balance restrictions.

It is known that obese people, regardless of age, have greater absolute maximum muscle strength in anti-gravity muscles compared to non-obese counterparts this is valid only for lower limbs, since upper limb strength reveals no statistical difference between obese and normal-weight people Maffiuletti et al.

This observation has been interpreted as adiposity being a chronic overload stimulus for muscles, thus making muscles stronger and bigger. However, it is noteworthy that when muscular strength is normalized to total body mass, the obese people seem to be overall weaker than their lean control individuals.

Notwithstanding, the existing literature shows considerable controversy on this matter Tomlinson et al. For this reason, the real effect of obesity on skeletal muscle size, structure, and function remains elusive.

Although there is no consensus regarding accurate measures of obesity-associated muscle damage or quality, it is worth mentioning that obesity does have been shown to generate a negative impact on skeletal musculature through adolescence to young and old adulthood Blimkie et al.

Obviously, the relevance for reduced muscle performance is higher for older people, as they are generally affected by reduced functional capacity.

This includes impairments in walking, impaired ability to go up and downstairs, and difficulty with rising from chair or bed. Similarly, there is an augmented risk to suffer joint pathologies, such as knee osteoarthritis, due to joint overload and reduced muscle strength Cooper et al.

All these conditions represent a clear sign of poor quality of life for older people, which is worsened by obesity. In connection to ectopic fat deposition, the accumulation of triglycerides intra-myocellularly and inter-myocellularly is known to cause lipotoxicity, insulin resistance, and impaired glucose metabolism.

The increased flux of fatty acids to the myocyte appears to be the link between muscle fat infiltration and insulin resistance and altered glucose metabolism.

It has been shown that when mitochondrial β-oxidation is overwhelmed due to an excess of free fatty acids entering the myocyte, metabolic intermediaries of fatty acids accumulate and finally impair insulin signaling Moro et al.

It has been shown that skeletal muscle fat infiltration, together with sarcopenia, is able to have not only metabolic consequences but also to impair the daily living, by diminishing mobility Katsanos and Mandarino, The effect of adipokines on the skeletal muscle has emerged as an important area of research.

It has been shown that adipokines including leptin, adiponectin, visfatin, and resistin are able to affect muscle insulin sensitivity Nicholson et al. There are several in vitro studies about the role of adipokines in the skeletal muscle metabolism and insulin sensitivity.

However, those studies have been carried out mainly using rodent skeletal muscle cells that are known to have different fiber composition and different metabolic characteristics than human skeletal muscle cells.

This may be the reason why reports about the role of adipokines in muscle function and insulin resistance result controversial. Beyond the effect of inflammation-associated adipokines on skeletal muscle, it is worth mentioning that under obesity conditions, the muscle becomes an inflammatory organ itself, able to secrete several circulating factors known as myokines that can act in either autocrine, paracrine or endocrine manner, thus affecting the metabolism of both muscle and other organs.

The muscle is able to secrete several hundred of factors in response to contraction, which became a whole new paradigm for understanding the communication between muscles and the various organ systems, including adipose tissue, liver, pancreas, and brain.

It is worth to mention that some myokines exert their functions in the muscle itself and have been suggested to regulate skeletal muscle growth, repair, maintenance, and regeneration, in addition to mediating the health benefits of exercise for review see Pedersen, Obesity, at the population level, has been considered as a risk factor for the development of cardiovascular diseases such as coronary heart disease and heart failure.

Obesity-associated transition from asymptomatic subclinical left ventricle changes to overt dilated cardiomyopathy, irrespective of the coexistence of hypertension or diabetes mellitus, has been shown Wong and Marwick, Importantly, body fat distribution has been found to be more important than total fat composition on left ventricle adaptations to obesity, with excessive visceral fat causing adverse hemodynamics, concentric left ventricle remodeling, lower cardiac output, and higher systemic vascular resistance.

Lower-body subcutaneous fat has been found to cause eccentric left ventricle remodeling, higher cardiac output, and lower systemic vascular resistance, thus suggesting a protective role for subcutaneous adipose tissue, highlighting the importance of adipose tissue quality and function more than just the amount of body fat per se Kim et al.

In this regard, one hypothesis holds that the presence of insulin-sensitive subcutaneous adipose tissue protects the individual from ectopic accumulation of lipids and the development of metabolic syndrome Kim et al.

Cardiomyocyte hypertrophy and myocardial fat infiltration have also been demonstrated in obesity Ommen and Lopez-Jimenez, ; Samanta et al. In this sense, obesity-triggered ectopic fat deposition is considered as a predictive risk factor for cardiovascular disease.

The above mentioned ectopic fat accumulation in the liver and muscle together with the associated inflammation in particular constitutes a cardiovascular risk due to the associated insulin resistance and altered lipid and glucose metabolism.

Fat surrounding the heart and blood vessels and within the renal sinus has been linked to local toxic effects by several lines of evidence. The damaging effect of ectopic fat in the cardiovascular system has been attributed to two main mechanisms: 1 fat deposition around the heart pericardial or epicardial fat and coronary arteries, 2 lipid accumulation within the cardiomyocyte.

Pericardial, perivascular, pericoronary, and myocardial fat accumulation may lead to injury in blood vessels and heart directly by lipotoxicity and indirectly by cytokine secretion Lim and Meigs, Fat in the neck is the only fat depot in the upper-body that is considered as an additional cardiovascular risk, and it has been found to positively correlate with insulin resistance, visceral fat content, and metabolic syndrome Ben-Noun and Laor, ; Preis et al.

Interestingly, pericardial fat has been proposed to play roles in support and mechanical purpose for example, attenuation of vascular tension and torsion.

However, this fat depot, when gets considerably enlarged in obesity conditions, represents a mechanical hindrance for the beating heart, thus altering cardiac size and performance Iacobellis, In this connection, according to the Framingham Heart Study, pericardial fat is associated with coronary artery calcification and impaired cardiac function and conduction Rosito et al.

Accumulated fat around the coronary arteries and the heart appears to promote the atherosclerosis process, being associated with oxidative stress-related mechanisms. Myocardial fat accumulation has been associated with increased left ventricle mass, myocardiopathy and heart failure, mainly due to lipid-caused apoptosis of cardiomyocytes and the consequent cardiac dysfunction Szczepaniak et al.

A vast body of experimental, epidemiological, and clinical evidence supports the idea that obesity results harmful for both cardiovascular structure and function, mainly due to increased inflammation caused by deregulated adipokine production by a dysfunctional adipose tissue. In line with this, active endocrine and paracrine activity of cardiac ectopic fat depots within the cardiovascular system may be greatly responsible for insulin resistance and the atherosclerosis process.

Moreover, leptin, adiponectin, resistin, visfatin, omentin, IL-1, IL-6, plasminogen activator inhibitor-1, and TNFα, among several other circulating factors, have been reported to signal to the myocardium through either paracrine or autocrine pathways Iacobellis, Also, some anti-inflammatory factors secreted from perivascular fat adiponectin, adrenomedullin, and omentin have been demonstrated to play a key protective role in the regulation of the arterial vascular tone vasodilation , decreasing oxidative stress, improving endothelial function, and increasing insulin sensitivity Sacks and Fain, ; Piché and Poirier, It is important to highlight that secretion of pro-inflammatory adipokines is not only due to adipocyte secretion but also to secretion coming from adipose tissue-infiltrated macrophages Chatterjee et al.

In summary, beyond the contribution of visceral fat-secreted adipokines to cardiovascular disease, the presence of cardiac ectopic fat does also contribute: firstly, due to mechanical functions, and secondly, due to cardiac ectopic fat-released adipokines which would link the ectopic cardiac fat depot, the vasculature, and the myocardium, thus playing key roles in the pathogenesis of cardiovascular disease.

This section of the review is dedicated exclusively to the brain in the context of obesity. We will approach this topic from a variety of perspectives, including the anatomical and functional changes observed in the brain of obese individuals, the effects of obesity-associated circulating factors on the brain, the effects of obesity-associated morbidities on the brain and, last but not least, the effects of obesity-associated inflammation on the brain.

Differences in both gray and white matter have been reported in obese individuals compared to their normal-weight counterparts. Regarding the gray matter, it has been shown that it is reduced in brain regions such as the hippocampus, prefrontal cortex, and other subcortical regions in the context of obesity Stillman et al.

Interestingly, these differences have been attributed exclusively to excessive adiposity, since they have been shown to be still present even after controlling obesity-associated conditions, including diabetes Raji et al. Reduction in the volume of gray matter has been quite well established in several other brain regions of obese individuals using a variety of methodologies Pannacciulli et al.

There are studies reporting both obesity-associated reductions, as well as increases, in white matter in the context of obesity Pannacciulli et al.

Obesity and metabolic syndrome have undoubtedly been linked to deterioration in cognitive function. Moreover, clinical data have shown that obesity and diabetes mellitus are linked not only to cognitive decline but also to other brain disorders such as dementia, anxiety, and depression Simon et al.

Due to the difficulty to dissect the impact of each component of the obesity-associated altered metabolism on neuronal performance, it is assumed that brain structural changes, as well as the consequent cognitive impairment, are the result of the synergistic interplay between the different obesity-induced risk factors Yaffe, ; Yates et al.

Several models have been proposed that include the involvement of oxidative stress, inflammation, and abnormal brain lipid metabolism Yates et al. Peripheral insulin resistance has been shown to be accompanied with cognitive decline, mainly in memory and executive performance Heni et al.

Several studies have reported that obesity in midlife is associated with increased risk of mild cognitive impairment, altered executive functioning and short-term memory, and dementia Kivipelto et al.

Similar results have been shown in studies carried out in animal models of high-fat diet-induced obesity Murray et al.

In contrast, the association between obesity late in life and cognitive function is less clear. A recent and important study of more than men and women, followed for up to 28 years, has examined the link between obesity and cognitive change.

In this study, participants were assessed for BMI, waist circumference, signs of dementia, as well as cognitive decline Singh-Manoux et al. This difference may be due to the fact that BMI starts to decline several years before the diagnosis of dementia Singh-Manoux et al.

Vast epidemiological evidence supports a link between diabetes mellitus and cognitive dysfunction Gudala et al. However, it should be mentioned that this association, as well as the severity of cognitive decline, may vary according to the type of diabetes and the age diabetes starts.

Loss in glycemic control, evidenced by increased circulating HbA1c levels, has been found to be a risk factor for cognitive dysfunction, with behavioral and psychological manifestations Sakurai et al.

Clinical evidence has suggested that the duration of diabetes alone may not influence cognitive performance if glycemia is properly controlled over time West et al. Interestingly, beyond the chronically high glucose levels, blood glucose peaks have been related to both cognitive impairment and increased risk of dementia Geijselaers et al.

Additionally, observational studies have shown beneficial effects of some glucose-lowering treatments on cognitive performance. For example, metformin has been shown to improve cognitive performance in US diabetic veterans Orkaby et al. Leptin deficiency has been linked to alterations in brain volume and structure, and these alterations have been shown to be reversed by external leptin administration Matochik et al.

Leptin has been shown to have a direct impact on the hypothalamic nuclei which are responsible for the production of both orexigenic and anorexigenic peptides Qi et al. Indeed, leptin has been demonstrated to exert neurotrophic actions during the development of the hypothalamus, stimulating the growth of axons from the arcuate nucleus to other regions that control energy homeostasis, thus participating in the development of feeding circuits.

Interestingly, this developmental activity of leptin has been shown to depend on timing and duration of leptin exposure Bouret et al. Leptin has also been related to presynaptic neurotransmitter release and postsynaptic neurotransmitter sensitivity, and to the processes of memory and cognition, especially to hypothalamic and hippocampal functions Fewlass et al.

Alterations in hippocampal structure and function have been reported in animals with congenital leptin deficit, supporting a role for leptin in hippocampal development and function Li et al. Neurodegeneration, neurogenesis, synaptic plasticity as well as memory consolidation have been shown to be influenced by leptin action on the hippocampus Doherty, Also, leptin has been shown to enhance cognition through the regulation of hippocampal function.

Both in vivo and in vitro studies the latter in hippocampal slices have shown that exogenous leptin is able to induce long-term potentiation Shanley et al. Other in vitro studies have shown that leptin is able to induce synapse formation in cultured hippocampal neurons, thus providing a possible explanation for the long-term potentiation observed after leptin administration.

Studies in humans have shown that high leptin levels are negatively correlated with late-in-life dementia risk Harvey et al. Moreover, leptin has been shown to reduce extracellular levels of amyloid beta peptide Aβ; whose deposition is pathognomonic of AD both in vivo and in vitro Fewlass et al.

For these reasons, the elevation of leptin has been suggested as a therapeutic alternative for dementia Fewlass et al. Although animal studies are promising, further research is needed to assess whether these findings apply to human beings. Due to undetectable levels of adiponectin in the cerebrospinal fluid CSF , it was first thought that this hormone was not able to cross the BBB Pan et al.

However, several studies have shown that intravenous injection of adiponectin leads to detectable levels of the hormone in the CSF of patients with unspecified neurological disorders Kos et al. Indeed, as no HMW adiponectin has been detected in the CSF, it is now believed that only smaller forms of the adiponectin hormone can cross the BBB Kusminski et al.

Thus, the origin of brain associated adiponectin is still a matter of debate. Adiponectin plasma levels correlate inversely with obesity, insulin resistance and type-2 diabetes mellitus Hotta et al. Adiponectin has been shown to regulate proliferation, neurogenesis, and branching of hippocampal neural stem cells Zhang et al.

Also, it has been shown to exert a neuroprotective role against Aβ-induced oxidative stress in vitro Ng and Chan, Adiponectin deficiency in mice has shown to cause memory and spatial learning impairment, anxiety, and impaired fear conditioning, symptoms that are probably associated to the decreased synaptic protein levels, increased neuronal apoptosis and impaired insulin signaling found in those animals Ng et al.

Also, adiponectin-deficient mice have shown to suffer larger brain infarctions after ischemia and reperfusion compared with control animals, and adiponectin administration has shown to reduce the infarction size.

Thus neuroprotective effects have been attributed to this adipokine Nishimura et al. Adiponectin physiological levels are generally higher in females than in males and decrease in both sexes as age increases Ng and Chan, However, among women, those with higher plasma levels of adiponectin have shown to exhibit poorer performance in language and global cognition and to coincide with greater mild cognitive impairment diagnosis Wennberg et al.

Nevertheless, more studies are necessary to conclusively affirm that higher adiponectin plasma level is a trustable predictor of cognitive decline. Patients with AD have been observed to have decreased levels of adiponectin in CSF, compared to those found in healthy controls or even to patients with mild cognitive impairment.

However, adiponectin levels have been found to be increased in plasma of patients with mild cognitive impairment and AD, compared to that in controls. Thus, a loss of function of adiponectin signaling has been suggested to occur in the pathogenesis of AD Waragai et al. As mentioned before, the increased circulating levels of pro-inflammatory cytokines participate in obesity-induced systemic inflammation.

This systemic inflammation may participate in the development of cognitive decline and dementia. For example, IL-1β and IL-6 have been shown to disrupt cognition- and memory-related neuronal circuits Gemma and Bickford, Increased plasma levels of C-reactive protein and IL-6 have been identified in a meta-analysis performed by Koyama et al.

Peripheral cytokines have been shown to induce local production of cytokines in the brain Dantzer et al. It is important to highlight that all the obesity-associated morbidities mentioned before cardiovascular disease, diabetes, atherosclerosis, etc.

do impact on brain health. Obesity-derived vascular problems, such as atherosclerosis and arteriosclerosis, which are systemic diseases, are known to affect the steady blood flow of vessels that feed the brain, thus contributing to cognitive impairment or even stroke, where large areas of the brain die due to the stop in the blood flow of a major brain artery caused by a blood clot.

Vascular dementia has been shown to be caused by cerebrovascular disease, and compelling evidence has shown that cerebrovascular disease may be initiated by obesity Gorelick et al.

However, many aspects of the association between obesity and cerebrovascular disease are still poorly defined. Also, epidemiological studies have shown that cardiovascular risk factors such as obesity, hypertension, diabetes, and low physical activity negatively affect brain performance Wolf, ; Yano et al.

A longitudinal study from Gustafson and coworkers has shown lower BBB integrity in overweight or obese individuals, compared to normal-weight controls Gustafson et al.

Similar evidence has been presented from rodent studies Kanoski et al. Indeed, irregular heartbeat conditions such as arrhythmia or atrial fibrillation, as well as obstructive sleep apnea both highly prevalent in obese individuals , have been linked to increased risk of ischemic stroke and dementia development Zhang et al.

Epidemiological studies have linked type-2 diabetes mellitus with cognitive impairment and dementia, with insulin resistance and hyperglycemia as the probable mechanistic links Ott et al.

Similarly, several cross-sectional studies have confirmed the association between insulin resistance and cognitive decline van den Berg et al. Hyperglycemia has been associated with poor cognitive outcomes both in cross-sectional studies Yaffe et al. A very recent 6-year follow-up study from Hong and coworkers has found that insulin resistance is associated with diminished cognitive performance in older individuals Kong et al.

Also, data from prospective studies have shown that individuals with type-2 diabetes exhibit poorer performance in information-processing speed, memory, attention, and executive function compared to controls Hassing et al.

However, the evidence is controversial, and further interventional studies are needed to evaluate the effect of controlling insulin resistance and diabetes on cognitive dysfunction. Interestingly, obesity comorbidities have been shown to participate in the onset and progression of neurodegenerative diseases such as AD.

The complete mechanisms by which obesity influences the risk of AD is not entirely clear yet. However, epidemiological studies have demonstrated that type-2 diabetes increases the risk of AD Profenno et al. It is assumed that insulin resistance is a key causative factor for diabetes and it has been demonstrated that individuals with peripheral insulin resistance are more prone to develop AD and related pathologies Sims-Robinson et al.

Moreover, at the cellular and molecular level, insulin signaling has been demonstrated to interfere with Aβ degradation and deposition Carro et al.

Further, insulin deficiency has also been shown to promote tau phosphorylation, leading to the accumulation of neurofibrillary tangles Schubert et al. Accumulating evidence has shown that the brain itself develops insulin resistance due to the impairment in the insulin pathway Moloney et al.

In line with this, in vivo experimental data have shown that insulin resistance modifies cognitive performance even in the absence of diabetes Su et al. Moreover, insulin signaling impairment has been found in brains from AD patients Talbot et al.

Increased levels of amyloid proteins have been found in the plasma of obese individuals Lee et al. Also, higher expression levels of beta-amyloid precursor protein and tau, two pathognomonic features of AD, have been found in the hippocampus of morbidly obese patients, compared to non-obese controls Mrak, ; Nguyen et al.

On the other hand, numerous studies have demonstrated that high-fat diets contribute to the higher expression of AD markers in rodents Studzinski et al. Indeed, uncontrolled diabetes has also been linked to the risk of developing AD Xu et al.

Several aspects of brain function result affected by obesity-triggered inflammation. Periodic neuroinflammation is a necessary defense for the brain.

However, when neuroinflammation becomes prolonged or uncontrolled chronic neuroinflammation , it disrupts the normal protective barriers and leads to maladaptive synaptic plasticity and the development of different neurodegenerative disorders Purkayastha and Cai, It has long been accepted that the BBB keeps blood inflammatory cells monocytes and neutrophils from getting into the brain.

Therefore, microglia would be the only cells that mediate brain inflammation. However, it has become known that neutrophils and monocytes are able to infiltrate the injured brain and contribute to inflammation Jeong et al. Astrocytes are known to produce anti-inflammatory factors that recruit monocytes, and neurons are able to both positively or negatively modulate anti-inflammatory response Kim et al.

Thus, brain inflammation involves the coordinated efforts of several types of cells including microglia neutrophils, monocytes, astrocytes, and neurons. Chronic neuroinflammation has been shown to impair adult hippocampal neurogenesis, and the blockade of neuroinflammation has demonstrated to restore it Ekdahl et al.

Also, impaired neurogenesis has been found in the hypothalamus of high-fat diet-fed rodents, probably due to the chronic neuroinflammatory response Li et al. The complete mechanism is not fully understood, but stimulation of immune cells with the concomitant activation of the NF-kB pathway, and the release of interleukins and nitric oxide are thought to be involved Purkayastha and Cai, On the other hand, brain inflammation, mediated by inflammatory cells such as microglia and astrocytes, plays pivotal roles in regulating synaptic structure and function Mottahedin et al.

Synaptic disorganization is an integral part of several neurological disorders Ebrahimi-Fakhari and Sahin, Glial cells are thought to play a vital role in synaptic architecture and hence neuronal connectivity.

For this reason, factors that affect glial cells during development may also have long-term consequences on the synapse performance. Accordingly, an interaction between synaptic disorganization and immune function has been linked with cognitive weakness Delpech et al.

The BBB is known to actively participate in the inflammatory events and, conversely, the obesity-associated chronic inflammation also influences the BBB.

It has been suggested that the BBB disruption occurs well before the infiltration of immune cells to the site of inflammation. Once within the brain, these effector cells and their secreted factors act upon microglia, astrocytes, and pericytes, which are important components of the BBB, and collaborate to a further BBB disruption thus leading to neuronal damage Sonar and Lal, Chronic brain inflammation also has been linked to neurodegenerative disorders such as AD.

Aβ peptide accumulation in the brain parenchyma and blood vessels has been shown to promote both acute and chronic inflammatory responses which are mediated by astrocytes and microglia and which may finally cause neurodegeneration. However, the role of inflammation in AD is controversial, because inflammation has been found to have a beneficial role in the early stages of the disease.

Nevertheless, the chronic activation of the microglia has been linked to the increased generation of Aβ and also with tau phosphorylation Meraz-Ríos et al.

Overall, the inflammatory process in AD is characterized by changes in microglial morphology together with astrogliosis increased number, size, and motility of astrocytes. Studies in rodent models have shown that neuroinflammation is linked to early stages in tauopathies, even preceding tangle formation Yoshiyama et al.

Although the neuronal death associated with inflammation makes it a potential risk factor in the pathogenesis of AD, whether brain inflammation is the cause of or a secondary phenomenon to this disorder is unclear yet.

Obesity may serve as an amplifier or initiator of the chronic inflammation observed in AD patients, although further research is needed to clarify the specific contribution of obesity to the chronic brain inflammation observed at the onset and progression of AD.

The causes and impact of obesity on overall health are far from linear and point to a complex set of interactions. The ultimate impact of obesity on an individual appears to be the summation of the effects of adipose-derived factors adipokines, triglycerides, etc.

and indirect obesity effects hypertension, glycemic dysregulation, etc. and the physiology of the various organ systems of the body. Environmental factors and aging can accelerate or inhibit the effects of obesity on the various organ systems and tissues of the body, and this is an area of research that is rapidly expanding and identifying exciting results.

Given the rapid increase in both obesity and aging in the populations of most Western societies, it will be critical to move obesity research into the realm of translational interventions, whereby the negative impacts of obesity on health are delayed or prevented in an increasingly elderly population.

RU and JK contributed to conception and design of the review and wrote the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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