Therapeutic Intervention In Obesity Research Articles

Targeting Dlat-Trpv3 pathway by hyperforin elicits non-canonical promotion of adipose thermogenesis as an effective anti-obesity strategy

IntroductionPromoting adipose thermogenesis is considered as a promising therapeutic intervention in obesity. However, endeavors to develop anti-obesity medications by targeting the canonical thermogenesis regulatory pathway, particularly β3-adrenergic receptor (β3-AR)-dependent mechanism, have failed due to the off-target effects of β3-AR agonists, exacerbating the risk of cardiovascular disease. Hyperforin (HPF), a natural compound extracted from the traditional herbal St. John’s Wort, binds to Dihydrolipoamide s-acetyltransferase (Dlat) and exerts effective anti-obesity properties through promoting adipose thermogenesis. ObjectivesThe objective of this study was to investigate the oral efficacy and pharmacokinetics profile of HPF, and explore the detailed mechanism by which Dlat modulates HPF-mediated adipose thermogenesis. MethodsTo assess the anti-obesity efficacy of orally administered HPF in vivo, Dlat heterozygous knockout (Dlat+/-) mice and wild-type (WT) mice, both fed a high-fat diet (HFD), underwent a validation process that involved the use of metabolic cages, NMR analysis, and infrared imaging. Sprague Dawley rats were employed to determine the pharmacokinetic parameters of HPF. Seahorse assays, JC-1 staining, qPCR, and immunoblotting were performed to evaluate cellular thermogenic efficacy of HPF and Dlat in vitro. ResultsOur study uncovered a non-canonical thermogenesis pathway involving Dlat, transient receptor potential vanilloid 3 (Trpv3, a calcium channel) and AMPK. Dlat interacted with Trpv3 to activate it, resulting in an increase in intracellular calcium (Ca2+) and the activation of Camkkβ. Camkkβ then stimulated AMPK, leading to elevated Ucp1 expression and initiating adipose thermogenesis. HPF promoted thermogenesis in adipose tissues through enhancing the Dlat-Trpv3 interaction independently of β3­AR, causing minimal cardiac side effects. Notably, HPF’s thermogenic effects were reduced in Dlat+/- mice. Moreover, HPF exerted favorable oral bioavailability, a relatively long half-life, and extensive distribution within adipose tissues. ConclusionIn summary, our study demonstrates that HPF targets a novel mechanism for promoting adipose thermogenesis and exhibits potent and safe anti-obesity efficacy.

Neddylation and Its Target Cullin 3 Are Essential for Adipocyte Differentiation.

The ongoing obesity epidemic has raised awareness of the complex physiology of adipose tissue. Abnormal adipocyte differentiation results in the development of systemic metabolic disorders such as insulin resistance and diabetes. The conjugation of NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to target protein, termed neddylation, has been shown to mediate adipogenesis. However, much remains unknown about its role in adipogenesis. Here, we demonstrated that neddylation and its targets, the cullin (CUL) family members, are differentially regulated during mouse and human adipogenesis. Inhibition of neddylation by MLN4924 significantly reduced adipogenesis of 3T3-L1 and human stromal vascular cells. Deletion of NAE1, a subunit of the only NEDD8 E1 enzyme, suppressed neddylation and impaired adipogenesis. Neddylation deficiency did not affect mitotic cell expansion. Instead, it disrupted CREB/CEBPβ/PPARγ signaling, essential for adipogenesis. Interestingly, among the neddylation-targeted CUL family members, deletion of CUL3, but not CUL1, CUL2, or CUL4A, largely replicated the adipogenic defects observed with neddylation deficiency. A PPARγ agonist minimally rescued the adipogenic defects caused by the deletion of NAE1 and CUL3. In conclusion, our study demonstrates that neddylation and its targeted CUL3 are crucial for adipogenesis. These findings provide potential targets for therapeutic intervention in obesity and metabolic disorders.

The evolutionary conserved miR-137/325 tandem mediates obesity-induced hypogonadism and metabolic comorbidities by repressing hypothalamic kisspeptin

BackgroundObesity-induced hypogonadism (OIH) is a prevalent, but often neglected condition in men, which aggravates the metabolic complications of overweight. While hypothalamic suppression of Kiss1-encoded kisspeptin has been suggested to contribute to OIH, the molecular mechanisms for such repression in obesity, and the therapeutic implications thereof, remain unknown. MethodsA combination of bioinformatic, expression and functional analyses was implemented, assessing the role of the evolutionary-conserved miRNAs, miR-137 and miR-325, in mediating obesity-induced suppression of hypothalamic kisspeptin, as putative mechanism of central hypogonadism and metabolic comorbidities. The implications of such miR-137/325-kisspeptin interplay for therapeutic intervention in obesity were also explored using preclinical OIH models. ResultsMiR-137/325 repressed human KISS1 3’-UTR in-vitro and inhibited hypothalamic kisspeptin content in male rats, while miR-137/325 expression was up-regulated, and Kiss1/kisspeptin decreased, in the medio-basal hypothalamus of obese rats. Selective over-expression of miR-137 in Kiss1 neurons reduced Kiss1/ kisspeptin and partially replicated reproductive and metabolic alterations of OIH in lean mice. Conversely, interference of the repressive actions of miR-137/325 selectively on Kiss1 3’-UTR in vivo, using target-site blockers (TSB), enhanced kisspeptin content and reversed central hypogonadism in obese rats, together with improvement of glucose intolerance, insulin resistance and cardiovascular and inflammatory markers, despite persistent exposure to obesogenic diet. Reversal of OIH by TSB miR-137/325 was more effective than chronic kisspeptin or testosterone treatments in obese rats. ConclusionsOur data disclose that the miR-137/325-Kisspeptin repressive interaction is a major player in the pathogenesis of obesity-induced hypogonadism and a putative druggable target for improved management of this condition and its metabolic comorbidities in men suffering obesity. Significance statementUp to half of the men suffering obesity display also central hypogonadism, an often neglected complication of overweight that can aggravate the clinical course of obesity and its complications. The mechanisms for such obesity-induced hypogonadism remain poorly defined. We show here that the evolutionary conserved miR137/miR325 tandem centrally mediates obesity-induced hypogonadism via repression of the reproductive-stimulatory signal, kisspeptin; this may represent an amenable druggable target for improved management of hypogonadism and other metabolic complications of obesity.

Cognitive reappraisal of food craving and emotions: a coordinate-based meta-analysis of fMRI studies.

Growing evidence supports the effectiveness of cognitive reappraisal in down-regulating food desire. Still, the neural bases of food craving down-regulation via reappraisal, as well as their degree of overlap vs specificity compared with emotion down-regulation, remain unclear. We addressed this gap through activation likelihood estimation meta-analyses of neuroimaging studies on the neural bases of (i) food craving down-regulation and (ii) emotion down-regulation, alongside conjunction and subtraction analyses among the resulting maps. Exploratory meta-analyses on activations related to food viewing compared with active regulation and up-regulation of food craving have also been performed. Food and emotion down-regulation via reappraisal consistently engaged overlapping activations in dorsolateral and ventrolateral prefrontal, posterior parietal, pre-supplementary motor and lateral posterior temporal cortices, mainly in the left hemisphere. Its distinctive association with the right anterior/posterior insula and left inferior frontal gyrus suggests that food craving down-regulation entails a more extensive integration of interoceptive information about bodily states and greater inhibitory control over the appetitive urge towards food compared with emotion down-regulation. This evidence is suggestive of unique interoceptive and motivational components elicited by food craving reappraisal, associated with distinctive patterns of fronto-insular activity. These results might inform theoretical models of food craving regulation and prompt novel therapeutic interventions for obesity and eating disorders.

Adiposity Reduction by Cucumis melo var. gaettongchamoe Extract in High-Fat Diet-Induced Obese Mice.

This study investigated the anti-obesity effects of Cucumis melo var. gaettongchamoe (CG) in mice fed a high-fat diet (HFD). The mice received CG water extract (CGWE) treatment for 8 weeks, and changes in body weight and serum lipid levels were analyzed. The HFD + vehicle group showed a significant increase in body weight compared to the control group, while the HFD + CGWE and HFD + positive (orlistat) groups exhibited reduced body weight. Lipid profile analysis revealed lower levels of total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein cholesterol in the HFD + CGWE group compared to the HFD + vehicle group. The HFD + vehicle group had increased abdominal fat weight and fat content, whereas both HFD + CGWE groups showed significant reductions in abdominal fat content and adipocyte size. Additionally, CGWE administration downregulated mRNA expression of key proteins involved in neutral lipid metabolism. CGWE also promoted hepatic lipolysis, reducing lipid droplet accumulation in hepatic tissue and altering neutral lipid metabolism protein expression. Furthermore, CGWE treatment reduced inflammatory mediators and suppressed the activation of the mitogen-activated protein kinase pathway in hepatic tissue. In conclusion, CGWE shows promise as a therapeutic intervention for obesity and associated metabolic dysregulation, including alterations in body weight, serum lipid profiles, adipose tissue accumulation, hepatic lipolysis, and the inflammatory response. CGWE may serve as a potential natural anti-obesity agent.

Dopamine receptor D4 (DRD4) negatively regulates UCP1- and ATP-dependent thermogenesis in 3T3-L1 adipocytes and C2C12 muscle cells.

The activation of beige fat and muscle tissues is an interesting and encouraging target for therapeutic intervention in obesity owing to their remarkable lipolytic activity and energy-consuming futile cycles. This study examined the effect of dopamine receptor D4 (DRD4) on lipid metabolisms as well as UCP1- and ATP-dependent thermogenesis in Drd4-silenced 3T3-L1 adipocytes and C2C12 muscle cells. Silencing of Drd4, followed by quantitative real-time PCR, immunoblot analysis, immunofluorescence, and staining methods, were applied to evaluate the effects of DRD4 on diverse target genes and proteins of both cells. The findings showed that DRD4 was expressed in the adipose and muscle tissues of normal and obese mice. Furthermore, the knockdown of Drd4 upregulated the expression of brown adipocyte-specific genes and proteins while downregulating lipogenesis and the adipogenesis marker proteins. Drd4 silencing also upregulated the expression of key signaling molecules involved in ATP-dependent thermogenesis in both cells. This was further elucidated by mechanistic studies showing that a Drd4 knockdown mediates UCP1-dependent thermogenesis via the cAMP/PKA/p38MAPK pathway in 3T3-L1 adipocytes and UCP1-independent thermogenesis via the cAMP/SLN/SERCA2a pathway in C2C12 muscle cells. In addition, siDrd4 also mediates myogenesis via the cAMP/PKA/ERK1/2/Cyclin D3 pathway in C2C12 muscle cells. Silencing of Drd4 promotes β3-AR-dependent browning in 3T3-L1 adipocytes and α1-AR/SERCA-based thermogenesis through an ATP-consuming futile process in C2C12 muscle cells. Understanding the novel functions of DRD4 on adipose and muscle tissues in terms of its ability to enhance energy expenditure and regulate whole-body energy metabolism will aid in developing novel obesity intervention techniques.

LncRNA MIR99AHG enhances adipocyte differentiation by targeting miR-29b-3p to upregulate PPARγ

AimThe aim is to identify new long noncoding RNAs (lncRNAs) involved in adipocyte differentiation. MethodsHigh-throughput RNA sequencing of 3T3-L1 preadipocytes was carried out before and after differentiation to identify the target lncRNAs and miRNAs. The effects of lncRNA, miRNA and the network mechanism on adipocyte differentiation were evaluated in vitro and in vivo. Visceral adipose tissue (VAT) was collected from Chinese subjects with obesity or a normal body mass index (BMI), and the levels of lncRNAs, adipogenic genes and miRNAs were measured. ResultsMIR99AHG, miR-29b-3p were selected as the target lncRNA and miRNA. Short hairpin RNA against MIR99AHG inhibited the differentiation of 3T3-L1 preadipocytes, reduced the expression of the peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT enhancer-binding protein alpha (C/EBPα) and fatty acid binding protein 4 (FABP4) genes, upregulated the expression of miR-29b-3p. Overexpression of MIR99AHG showed the opposite effects. Overexpression of miR-29b-3p inhibited the differentiation of 3T3-L1 preadipocytes and decreased the PPARγ level, while inhibition of miR-29b-3p showed the opposite effects. MIR99AHG and PPARγ competed for binding to miR-29b-3p. In mice with high-fat diet-induced obesity, MIR99AHG and miR-29b-3p mRNA level were increased and decreased, respectively. Tail vein injection of adeno-associated virus 9-MIR99AHG-RNA interference (AAV9-MIR99AHG-RNAi) reduced the body weight, epididymal fat mass, MIR99AHG level and increased the expression of miR-29b-3p. The expression levels of MIR99AHG, PPARγ, C/EBPα and FABP4 in human visceral adipose tissue were higher in the obese group than in the normal weight group. ConclusionsMIR99AHG enhances adipogenesis by regulating miR-29b-3p and PPARγ, providing a new target for therapeutic intervention in obesity.

MiR-409-3p targets a MAP4K3-ZEB1-PLGF signaling axis and controls brown adipose tissue angiogenesis and insulin resistance.

Endothelial cells (ECs) within the microvasculature of brown adipose tissue (BAT) are important in regulating the plasticity of adipocytes in response to increased metabolic demand by modulating the angiogenic response. However, the mechanism of EC-adipocyte crosstalk during this process is not completely understood. We used RNA sequencing to profile microRNAs derived from BAT ECs of obese mice and identified an anti-angiogenic microRNA, miR-409-3p. MiR-409-3p overexpression inhibited EC angiogenic properties; whereas, its inhibition had the opposite effects. Mechanistic studies revealed that miR-409-3p targets ZEB1 and MAP4K3. Knockdown of ZEB1/MAP4K3 phenocopied the angiogenic effects of miR-409-3p. Adipocytes co-cultured with conditioned media from ECs deficient in miR-409-3p showed increased expression of BAT markers, UCP1 and CIDEA. We identified a pro-angiogenic growth factor, placental growth factor (PLGF), released from ECs in response to miR-409-3p inhibition. Deficiency of ZEB1 or MAP4K3 blocked the release of PLGF from ECs and PLGF stimulation of 3T3-L1 adipocytes increased UCP1 expression in a miR-409-3p dependent manner. MiR-409-3p neutralization improved BAT angiogenesis, glucose and insulin tolerance, and energy expenditure in mice with diet-induced obesity. These findings establish miR-409-3p as a critical regulator of EC-BAT crosstalk by modulating a ZEB1-MAP4K3-PLGF signaling axis, providing new insights for therapeutic intervention in obesity.

Novel Roles of Follistatin/Myostatin in Transforming Growth Factor-β Signaling and Adipose Browning: Potential for Therapeutic Intervention in Obesity Related Metabolic Disorders.

Obesity is a global health problem and a major risk factor for several metabolic conditions including dyslipidemia, diabetes, insulin resistance and cardiovascular diseases. Obesity develops from chronic imbalance between energy intake and energy expenditure. Stimulation of cellular energy burning process has the potential to dissipate excess calories in the form of heat via the activation of uncoupling protein-1 (UCP1) in white and brown adipose tissues. Recent studies have shown that activation of transforming growth factor-β (TGF-β) signaling pathway significantly contributes to the development of obesity, and blockade or inhibition is reported to protect from obesity by promoting white adipose browning and increasing mitochondrial biogenesis. Identification of novel compounds that activate beige/brown adipose characteristics to burn surplus calories and reduce excess storage of fat are actively sought in the fight against obesity. In this review, we present recent developments in our understanding of key modulators of TGF-β signaling pathways including follistatin (FST) and myostatin (MST) in regulating adipose browning and brown adipose mass and activity. While MST is a key ligand for TGF-β family, FST can bind and regulate biological activity of several TGF-β superfamily members including activins, bone morphogenic proteins (BMP) and inhibins. Here, we review the literature supporting the critical roles for FST, MST and other proteins in modulating TGF-β signaling to influence beige and brown adipose characteristics. We further review the potential therapeutic utility of FST for the treatment of obesity and related metabolic disorders.

UCP1-dependent and UCP1-independent metabolic changes induced by acute cold exposure in brown adipose tissue of mice

BackgroundBrown adipose tissue (BAT) is a site of metabolic thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1) and represents a target for a therapeutic intervention in obesity. Cold exposure activates UCP1-mediated thermogenesis in BAT and causes drastic changes in glucose, lipid, and amino acid metabolism; however, the relationship between these metabolic changes and UCP1-mediated thermogenesis is not fully understood. MethodsWe conducted metabolomic and GeneChip array analyses of BAT after 4-h exposure to cold temperature (10 °C) in wild-type (WT) and UCP1-KO mice. ResultsCold exposure largely increased metabolites of the glycolysis pathway and lactic acid levels in WT, but not in UCP1-KO, mice, indicating that aerobic glycolysis is enhanced as a consequence of UCP1-mediated thermogenesis. GeneChip array analysis of BAT revealed that there were 2865 genes upregulated by cold exposure in WT mice, and 838 of these were upregulated and 74 were downregulated in UCP1-KO mice. Pathway analysis revealed the enrichment of genes involved in fatty acid (FA) β oxidation and triglyceride (TG) synthesis in both WT and UCP1-KO mice, suggesting that these metabolic pathways were enhanced by cold exposure independently of UCP1-mediated thermogenesis. FA and cholesterol biosynthesis pathways were enhanced only in UCP1-KO mice. Cold exposure also significantly increased the BAT content of proline, tryptophan, and phenylalanine amino acids in both WT and UCP1-KO mice. In WT mice, cold exposure significantly increased glutamine content and enhanced the expression of genes related to glutamine metabolism. Surprisingly, aspartate was almost completely depleted after cold exposure in UCP1-KO mice. Gene expression analysis suggested that aspartate was actively utilized after cold exposure both in WT and UCP1-KO mice, but it was replenished from intracellular N-acetyl-aspartate in WT mice. ConclusionsThese results revealed that cold exposure induces UCP1-mediated thermogenesis-dependent glucose utilization and UCP1-independent active lipid metabolism in BAT. In addition, cold exposure largely affects amino acid metabolism in BAT, especially UCP1-dependently enhances glutamine utilization. These results contribute a comprehensive understanding of UCP1-mediated thermogenesis-dependent and thermogenesis-independent metabolism in BAT.

1724-P: MicroRNA Regulation of Endothelial Cell Secretion of Placental Growth Factor and Adipose Browning

Brown adipose tissue (BAT), a highly vascularized, thermogenic tissue, converts chemical energy into heat. The ability of BAT to expand based on the metabolic demand, known as plasticity, plays a critical role in the regulation of whole body energy balance. Endothelial cells (ECs) within the microvasculature of the adipose tissue play an important role in aiding BAT retain plasticity by actively modulating the angiogenic response. However, the mechanism of EC-adipocyte cross-talk during this process is not completely understood. In BAT ECs of obese mice, we have previously identified an anti-angiogenic microRNA, miR-409-3p, using a RNA-seq profiling approach. We now show that miR-409-3p targets MAP4K3 to confer its anti-angiogenic effects in ECs. Overexpression of miR-409-3p markedly decreased MAP4K3 expression in ECs, whereas inhibition of miR-409-3p had the opposite effects. SiRNA knockdown of MAP4K3 expression in ECs phenocopied the effects of miR-409-3p overexpression and significantly decreased cell proliferation and migration. Adipocytes co-cultured with conditioned media from ECs deficient in miR-409-3p showed increased expression of brown fat markers UCP1 and Cidea by RT-qPCR and Western. By multiplex ELISA, we identified a pro-angiogenic growth factor, Placental Growth Factor (PLGF), that is released from ECs in response to miR-409-3p deficiency. PLGF stimulation of 3T3-L1 adipocytes differentiated them into brown adipocytes. Furthermore, siRNA knockdown of MAP4K3 blocked the release of PLGF from ECs. Co-culturing conditioned media from ECs deficient in PLGF expression by siRNA silencing significantly decreased UCP1 expression in 3T3-L1 adipocytes, whereas conditioned media from ECs deficient both in miR-409-3p and PLGF further decreased UCP1 expression showing dependency for miR-409-3p regulated pathways. MiR-409-3p plays a key role in EC-BAT crosstalk by modulating PLGF, an effect that could be exploited for therapeutic intervention in obesity. Disclosure D. Pérez-Cremades: None. D.R. Becker-Greene: None. H. Li: None. W. Wu: None. C.O. Aydogan: None. D. Ozdemir: None. M.W. Feinberg: None. B. Icli: None. Funding American Diabetes Association (1-16-JDF-046 to B.I.)

Distinct Fractions of an Artemisia scoparia Extract Contain Compounds With Novel Adipogenic Bioactivity.

Adipocytes are important players in metabolic health and disease, and disruption of adipocyte development or function contributes to metabolic dysregulation. Hence, adipocytes are significant targets for therapeutic intervention in obesity and metabolic syndrome. Plants have long been sources for bioactive compounds and drugs. In previous studies, we screened botanical extracts for effects on adipogenesis in vitro and discovered that an ethanolic extract of Artemisia scoparia (SCO) could promote adipocyte differentiation. To follow up on these studies, we have used various separation methods to identify the compound(s) responsible for SCO's adipogenic properties. Fractions and subfractions of SCO were tested for effects on lipid accumulation and adipogenic gene expression in differentiating 3T3-L1 adipocytes. Fractions were also analyzed by Ultra Performance Liquid Chromatography- Mass Spectrometry (UPLC-MS), and resulting peaks were putatively identified through high resolution, high mass accuracy mass spectrometry, literature data, and available natural products databases. The inactive fractions contained mostly quercetin derivatives and chlorogenates, including chlorogenic acid and 3,5-dicaffeoylquinic acid, which had no effects on adipogenesis when tested individually, thus ruling them out as pro-adipogenic bioactives in SCO. Based on these studies we have putatively identified the principal constituents in SCO fractions and subfractions that promoted adipocyte development and fat cell gene expression as prenylated coumaric acids, coumarin monoterpene ethers, 6-demethoxycapillarisin and two polymethoxyflavones.

MiR-144-3p Promotes Adipogenesis Through Releasing C/EBPα From Klf3 and CtBP2.

MicroRNAs (miRNAs), a class of small non-coding RNAs, have been proved as novel and potent regulators of adipogenesis. A previous study has found out that miR-144-3p was a biomarker of type 2 diabetes, but the role of miR-144-3p in regulating adipogenesis was still unclear. In the present study, the expression of miR-144-3p increased in obese mice and during the 3T3-L1 differentiation process. Overexpression of miR-144-3p suppressed the expression of cell cycle regulatory factors and inhibited pre-adipocytes proliferation. Besides, overexpression of miR-144-3p accelerated lipid accumulation in adipocytes and positively regulated adipogenesis, which was also accompanied by increasing the expression of genes related to fatty acid synthesis and decreasing the expression of genes involved in fatty acid oxidation. Furthermore, luciferase activity assays indicated that miR-144-3p directly targeted Klf3 and CtBP2. The process was also confirmed by the mRNA and protein expression of Klf3 and CtBP2, which were suppressed by miR-144-3p. Furthermore, miR-144-3p targeting Klf3/CtBP2 would induce C/EBPα activity by releasing corepressors (Klf3 and CtBP2) from its promoter region. Moreover, we also observed that miR-144-3p could promote adipogenesis in mice injected with miR-144-3p agomir through tail-vein injection. Taken together, these results support that miR-144-3p can facilitate adipogenesis both in vitro and in vivo, which implies that miR-144-3p could be a target for therapeutic intervention in obesity and metabolic syndrome in the future.

MicroRNA-200b regulates preadipocyte proliferation and differentiation by targeting KLF4

MicroRNAs (miRNAs) are small, non-coding RNAs that affect the post-transcriptional regulation of a variety of biological pathways. A previous study found out that miR-200b was important in the metabolism of obesity, but the mechanism of miR-200b regulateing adipogenesis is not fully understood.. In the present study, we observed that miR200b expression decreased both in obese mice and during the process of 3T3-L1 adipogenic differentiation. Overexpression of miR-200b promoted adipocyte proliferation by regulating the expression of cell cycle-regulated factors.Furthermore, overexpression of miR-200b reduced lipid accumulation and triglyceride content in adipocytes, and accompanied by a marked decrease in the expression of adipocyte-specific genes involved in fatty acid synthesis. Luciferase activity assays confirmed that miR-200b regulated adipocyte differentiation by directly targeting KLF4, and miR-200b suppressed the expression of KLF4 in both mRNA level and protein level. Moreover, the expression levels of downstream genes of KLF4, such as C/EBPβ, C/EBPα, KLF5 and PPARγ, were decreased in 3T3-L1 cells by miR-200b overexpression. Taken together, these results indicate that miR-200b may be involved in adipogenesis and could be a target for therapeutic intervention in obesity and metabolic syndrome.

Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease

Brown fat is emerging as an interesting and promising target for therapeutic intervention in obesity and metabolic disease. Activation of brown fat in humans is associated with marked improvement in metabolic parameters such as levels of free fatty acids and insulin sensitivity. Skeletal muscle is another important organ for thermogenesis, with the capacity to induce energy-consuming futile cycles. In this Review, we focus on how these two major thermogenic organs - brown fat and muscle - act and cooperate to maintain normal body temperature. Moreover, in the light of disease-relevant mechanisms, we explore the molecular pathways that regulate thermogenesis in brown fat and muscle. Brown adipocytes possess a unique cellular mechanism to convert chemical energy into heat: uncoupling protein 1 (UCP1), which can short-circuit the mitochondrial proton gradient. However, recent research demonstrates the existence of several other energy-expending 'futile' cycles in both adipocytes and muscle, such as creatine and calcium cycling. These mechanisms can complement or even substitute for UCP1-mediated thermogenesis. Moreover, they expand our view of cold-induced thermogenesis from a special feature of brown adipocytes to a more general physiological principle. Finally, we discuss how thermogenic mechanisms can be exploited to expend energy and hence offer new therapeutic opportunities.

Mini-Review: The Contribution of Intermediate Phenotypes to GxE Effects on Disorders of Body Composition in the New OMICS Era.

Studies of gene-environment (GxE) interactions describe how genetic and environmental factors influence the risk of developing disease. Intermediate (molecular or clinical) phenotypes (IPs) are traits or metabolic biomarkers that mediate the effects of gene-environment influences on risk behaviors. Functional systems genomics discovery offers mechanistic insights into how DNA variations affect IPs in order to detect genetic causality for a given disease. Disorders of body composition include obesity (OB), Type 2 diabetes (T2D), and osteoporosis (OSTP). These pathologies are examples of how a GxE interaction contributes to their development. IPs as surrogates for inherited genotypes play a key role in models of genetic and environmental interactions in health outcomes. Such predictive models may unravel relevant genomic and molecular pathways for preventive and therapeutic interventions for OB, T2D, and OSTP. Annotation strategies for genomes, in contrast to phenomes, are well advanced. They generally do not measure specific aspects of the environment. Therefore, the concepts of deep phenotyping and the exposome generate new avenues to exploit with high-resolution technologies for analyzing this sophisticated phenome. With the successful characterization of phenomes, exposomes, and genomes, environmental and genetic determinants of chronic diseases can be united with multi-OMICS studies that better examine GxE interactions.

Down-regulation of miRNAs in the brain and development of diet-induced obesity

Novel therapeutic interventions for obesity and comorbid conditions require knowledge of the molecular elements playing a role in the development of obesity. Chronic low-grade inflammation has been consistently reported in obese individuals. In this study, we first determined whether key molecular modulators of inflammation, microRNA-155 (miR-155) and microRNA-146a (miR-146a), are regulated by an obesogenic diet within brain regions associated with reward, metabolism and energy balance. C57BL/6J mice were chronically exposed to a high-fat diet (HFD) or a standard chow (CTL). Significant reductions in the levels of miR-155 (82%) and miR-146a (41%) levels were observed within the nucleus accumbens of HFD mice compared to CTL. Further analysis of miR-155 regulation showed no significant changes in levels across peripheral tissue (white adipose, spleen, kidney or liver) between HFD and CTL mice. The effect of lower miR-155 on the development of obesity was determined by exposing wild-type (WT) and miR-155 knockout mice (miR-155 KO) to HFD. Male miR-155 KO gained significantly more weight than WT littermates. Metabolic analyses revealed that miR-155 KO significantly ate more HFD compared to WT, without differing in other metabolic measures including energy expenditure. Together, these data show that miR-155 is physiologically down-regulated after intake of an obesogenic diet, and that loss of miR-155 increases intake of an obesogenic diet. Moreover, these findings shed light on a potential miRNA-based mechanism contributing to the development of diet-induced obesity.

Effect of obesity on assisted reproductive treatment outcomes and its management: a literature review

Key content Obesity is associated with infertility and poor obstetric outcomes. The current trends of advanced maternal age and rising obesity rates contribute indirectly to the growing demand for fertility treatment and assisted reproduction treatment (ART), posing clinical and ethical dilemmas for fertility service providers. The live‐birth rate, after ART, is significantly lower in obese women than non‐obese women, possibly due to impaired oocyte quality and/or defective endometrial receptivity. Poor ART outcomes correlate positively with the severity of obesity. Management of obesity‐related infertility should include diet, exercise, cognitive behavioural interventions and possibly adjunctive pharmacotherapy. Bariatric surgery may benefit morbidly obese women who struggle to lose weight otherwise. Randomised controlled trials are required to clarify the effects of various therapeutic interventions for obesity on ART outcomes. Learning objectives To understand the association of obesity and infertility with ART outcomes. To learn the principles of obesity‐related infertility management. Ethical issues To understand the ethical challenges in the provision of ART for obese women and to inform the stance of professional bodies, such as the British Fertility Society and the European Society of Human Reproduction and Embryology.

Epigallocatechin Gallate Inhibits Mouse Mesenchymal Stem Cell Differentiation to Adipogenic Lineage

Epigallocatechin gallate (EGCG) is a major component of green tea polyphenols having a potent anti-oxidant potential. Besides inhibiting the growth of many cancer cell types and inducing proliferation and differentiation in keratinocytes, it has been shown to promote reduction of body fat. The fact that mesenchymal stem cells (MSCs) have ability to self-renew and differentiate into the cells of mesodermal lineages, such as fat and bone, it is, thus, possible that EGCG may directly be involved in affecting fat metabolism through its effect on mesenchymal stem cells. Hence, with this aim, the present study was designed to determine the effect of EGCG on mouse mesenchymal stem cells, C3H10T1/2 cells differentiation into adipocytes. To understand this process, the cells were incubated with varying concentrations of EGCG (1 μM, 5 μM, 10 μM, 50 μM) in the presence and /or absence of adipogenic medium for 9 days. The results demonstrated that, EGCG inhibited the cells proliferation, migration and also prevented their differentiation to adipogenic lineage. These effects were analyzed through the inhibition of wound healing activity, reduction in Oil red O stained cells, together with decrease in the expression of Adipisin gene following EGCG treatment. These observations thus demonstrated anti-adipogenic effect of EGCG with a possibility of its role in the therapeutic intervention of obesity.

Differences in Insula and Pre-/Frontal Responses during Reappraisal of Food in Lean and Obese Humans.

Brain regions involved in the reappraisal of tasty but unhealthy foods are of special interest for the development of new therapeutic interventions for obesity, such as non-invasive brain stimulation or neurofeedback. Here, we visually presented food items (i.e., high/low caloric) to obese and lean individuals during electroencephalogram (EEG) recordings, while they either admitted or regulated their food desire. During admitting the desire for low and high calorie foods, obese as well as lean individuals showed higher activity in the left dorsolateral prefrontal cortex (DLPFC), whereas the right frontal operculum was involved in the reappraisal of the same foods, suggesting interplay between executive control and gustatory regions. Only in lean participants, we found an interaction between calorie content and the regulate/admit conditions in bilateral anterior insular cortices, suggesting that the anterior insula, assumed to primarily host gustatory processes, also underpins higher cognitive processes involved in food choices, such as evaluating the foods’ calorie content for its reappraisal.