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Nonalcoholic fatty liver disease comprises a wide spectrum of liver injuries from simple steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is defined when liver steatosis is associated with inflammation, hepatocyte damage, and fibrosis. A genetic predisposition and environmental insults (ie, dietary habits, obesity) are putatively responsible for NASH progression. Here, we present the impact of the lipid-sensing nuclear receptors in the pathogenesis and treatment of NASH. In detail, we discuss the pros and cons of the putative transcriptional action of the fatty acid sensors (peroxisome proliferator-activated receptors), the bile acid sensor (farnesoid X receptor), and the oxysterol sensor (liver X receptors) in the pathogenesis and bona fide treatment of NASH.

Obesity is a growing epidemic worldwide, and it is also considered a major environmental factor contributing to the pathogenesis of inflammatory skin diseases, including psoriasis (PSO) and atopic dermatitis (AD). Moreover, obesity worsens the course and impairs the treatment response of these inflammatory skin diseases. Emerging evidence highlights that hypertrophied adipocytes and infiltrated immune cells secrete a variety of molecules, including fatty acids and adipokines, such as leptin, adiponectin, and a panel of cytokines/chemokines that modulate our immune system. In this review, we describe how adipose hypertrophy leads to a chronic low-grade inflammatory state in obesity and how obesity-related inflammatory factors are involved in the pathogenesis of PSO and/or AD. Finally, we discuss the potential role of antimicrobial peptides, mechanical stress and impairment of epidermal barrier function mediated by fast expansion, and dermal fat in modulating skin inflammation. Together, this review summarizes the current literature on how obesity is associated with the pathogenesis of PSO and AD, highlighting the potentially important but overlooked immunomodulatory role of adipose tissue in the skin.

Objective Obesity represents a growing health problem that is reaching pandemic dimensions and lacks effective cures, thus highlighting an urgent need for better mechanistic understanding and new therapeutic strategies. Unlike transcription, the function of translation in obesity has hardly been investigated. Here, we fill this knowledge gap by pinpointing a crucial function for gene regulation at the step of translation in diet-induced obesity. Methods We performed studies with human adipose tissue, high-fat-diet-induced obese mice and rats, CPEB4-knockout mice, and adipocyte lines. Cells were transfected with small-interfering RNAs that knockdown CPEB4. Transcriptome-wide identification and validation of CPEB4 targets in adipocytes were obtained by RNA-protein coimmunoprecipitation and high-throughput sequencing. The effect of CPEB4 depletion on high-fat-diet-induced dysbiosis was determined by 16S ribosomal-RNA gene sequencing and microbiome bioinformatics. Results We show that cytoplasmic polyadenylation element-binding protein 4 (CPEB4), which controls the translation of specific mRNAs by modulating their poly(A) tails, is highly expressed in visceral fat of obese but not lean humans and rodents (mice and rats), where it orchestrates an essential post-transcriptional reprogramming for aggravation of high-fat-diet-induced obesity. Mechanistically, CPEB4 overexpression in obese adipocytes activates the translation of factors essential for adipose tissue expansion (Cebpb, Stat5a) and adipocyte-intrinsic immune-like potential (Ccl2, Tlr4), as demonstrated by RNA-immunoprecipitation and high-throughput sequencing and experimentally validated in vivo. Consistently blocking CPEB4 production in knockout mice protects against diet-induced body weight gain and reduces adipose tissue enlargement and inflammation. In addition, the depletion of CPEB4 specifically in obese adipocytes using short hairpin RNAs decreases cell differentiation, lipid accumulation, and the proinflammatory and migratory capacity of macrophages. The absence of CPEB4 also attenuates high-fat diet-induced dysbiosis, shaping the microbiome composition toward a more beneficial profile, as shown by microbiome bioinformatics analysis. Conclusion Our study identifies CPEB4 as a driver and therapeutic target to combat obesity., Highlights • CPEB4 expression is elevated in adipose tissue from obese patients and rodents. • CPEB4 overexpression is required for the abnormal obesity-associated phenotype. • Targeting CPEB4 reduces predisposition to diet-induced obesity. • Targeting CPEB4 alleviates obesity-associated microbiome dysbiosis. • CPEB4 is an attractive therapeutic target for treating obesity and its sequelae.

Triglycerides are carried in the bloodstream as the components of very low-density lipoproteins and chylomicrons. These circulating triglycerides are primarily hydrolyzed in muscle and adipose tissue by the enzyme lipoprotein lipase (LPL). The activity of LPL is regulated by numerous mechanisms, including by three members of the angiopoietin-like protein family: ANGPTL3, ANGPTL4, and ANGPTL8. In this review, we discuss the recent literature concerning the role and mechanism of action of ANGPTL4 in lipid metabolism. ANGPTL4 is a fasting- and lipid-induced factor secreted by numerous cells, including adipocytes, hepatocytes, (cardio)myocytes, and macrophages. In adipocytes, ANGPTL4 mediates the fasting-induced repression of LPL activity by promoting the unfolding of LPL, leading to the cleavage and subsequent degradation of LPL. The inhibition of LPL by ANGPTL4 is opposed by ANGPTL8, which keeps the LPL active after feeding. In macrophages and (cardio) myocytes, ANGPTL4 functions as a lipid-inducible feedback regulator of LPL-mediated lipid uptake. In comparison, in hepatocytes, ANGPTL4 functions as a local inhibitor of hepatic lipase and possibly as an endocrine inhibitor of LPL in extra-hepatic tissues. At the genetic level, loss-of-function mutations in ANGPTL4 are associated with lower plasma triglycerides and higher plasma HDL-C levels, and a reduced risk of coronary artery disease, suggesting that ANGPTL4 is a viable pharmacological target for reducing cardiovascular risk. Whole-body targeting of ANGPTL4 is contraindicated because of severe pathological complications, whereas liver-specific inactivation of ANGPTL4, either as monotherapy or coupled to anti-ANGPTL3 therapies might be a suitable strategy for lowering plasma triglycerides in selected patient groups. In conclusion, the tissue-specific targeting of ANGPTL4 appears to be a viable pharmacological approach to reduce circulating triglycerides.

Adipose tissue dysfunction is a hallmark of obesity and contributes to obesity-related sequelae such as metabolic complications and insulin resistance. Compelling evidence indicates that adipose-tissue-specific gene expression is influenced by gene interactions with proximal and distal cis-regulatory elements; the latter exert regulatory effects via three-dimensional (3D) chromosome conformation. Recent advances in determining the regulatory mechanisms reveal that compromised epigenomes are molecularly interlinked to altered cis-regulatory element activity and chromosome architecture in the adipose tissue. This review summarizes the roles of epigenomic components, particularly DNA methylation, in transcriptional rewiring in adipose tissue. In addition, we discuss the emerging roles of DNA methylation in the maintenance of 3D chromosome conformation and its pathophysiological significance concerning adipose tissue function.

Indigestible polysaccharides, such as dietary fibers, benefit the host by improving the intestinal environment. Short-chain fatty acids (SCFAs) produced by gut microbial fermentation from dietary fibers exert various physiological effects. The bacterial polysaccharide curdlan benefits the host intestinal environment, although its effect on energy metabolism and SCFA production remains unclear. Hence, this study aimed to elucidate the effect of curdlan intake on gut microbial profiles, SCFA production, and energy metabolism in a high-fat diet (HFD)-induced obese mouse model. Gut microbial composition of fecal samples from curdlan-supplemented HFD-fed mice indicated an elevated abundance of Bacteroidetes, whereas a reduced abundance of Firmicutes was noted at the phylum level compared with that in cellulose-supplemented HFD-fed mice. Moreover, curdlan supplementation resulted in an abundance of the family Bacteroidales S24-7 and Erysipelotrichaceae, and a reduction in Deferribacteres in the feces. Furthermore, curdlan supplementation elevated fecal SCFA levels, particularly butyrate. Although body weight and fat mass were not affected by curdlan supplementation in HFD-induced obese mice, HFD-induced hyperglycemia was significantly suppressed with an increase in plasma insulin and incretin GLP-1 levels. Curdlan supplementation elevated fecal bile acid and SCFA production, improved host metabolic functions by altering the gut microbial composition in mice., Highlights • Curdlan improves gut microbial composition in high-fat diet-fed (HFD) mice. • The effects of HFD-induced hyperglycemia are mitigated by curdlan supplementation. • Curdlan supplementation increases plasma insulin and GLP-1 levels. • Curdlan increases fecal short-chain fatty acids (SCFAs) and secondary bile acids.

Coronavirus disease 2019 (COVID-19) continues to have a devastating effect on a global scale. COVID-19 variants continue to arise and counteract vaccination efficacy. As such, preventative health measures, such as social distancing and stay at home mandates, will continue for the foreseeable future. Evidence on those at greatest risk for poor outcomes if infected with COVID-19 has rapidly come to light. It has become clear that those with unhealthy lifestyle characteristics, chronic disease risk factors and/or a confirmed diagnosis of one or more chronic conditions are at greatest risk for hospitalization, intensive care unit admission, mechanical ventilation, and death if infected with COVID-19. The cytokine storm is a phenomenon that has been posited as a pathophysiologic response to COVID-19 infection that leads to poor outcomes. The current graphical review illustrates the association between unhealthy lifestyle characteristics and increased vulnerability to the cytokine storm as well as the physiologic mechanisms healthy living behaviors elicit and decrease risk for the cytokine storm. Through this graphical review, we will demonstrate unhealthy lifestyle characteristics, chronic disease risk factors and diagnoses, and COVID-19 outcomes are intricately linked, creating a new global syndemic. It is also clear that a primary way to uncouple this syndemic is through increasing healthy living behaviors, as illustrated in this graphical review. Moving forward, healthy living medicine should be practiced with renewed vigor to improve human resiliency to health threats posed by both chronic disease and viral infections.

Obesity is increasing in an alarming rate worldwide, which causes higher risks of some diseases, such as type 2 diabetes, cardiovascular diseases, and cancer. Current therapeutic approaches, either pancreatic lipase inhibitors or appetite suppressors, are generally of limited effectiveness. Brown adipose tissue (BAT) and beige cells dissipate fatty acids as heat to maintain body temperature, termed non-shivering thermogenesis; the activity and mass of BAT and beige cells are negatively correlated with overweight and obesity. The existence of BAT and beige cells in human adults provides an effective weight reduction therapy, a process likely to be amenable to pharmacological intervention. Herein, we combed through the physiology of thermogenesis and the role of BAT and beige cells in combating with obesity. We summarized the thermogenic regulators identified in the past decades, targeting G protein-coupled receptors, transient receptor potential channels, nuclear receptors and miscellaneous pathways. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up-to-date knowledge from the biological importance of thermogenesis in energy homeostasis to the representative thermogenic regulators for treating obesity. Thermogenic regulators might have a large potential for further investigations to be developed as lead compounds in fighting obesity., Graphical abstract Brown adipose tissue (BAT) and beige cells dissipates fatty acids as heat, termed non-shivering thermogenesis, which has emerged as a potential therapeutically way to treat obesity. The current review provides a comprehensive and up-to-date of knowledge from the biological importance of thermogenesis to the representative thermogenic regulators for treating obesity.fx1

Objective Nonalcoholic steatohepatitis (NASH) is closely associated with metabolic syndrome and increases the risk for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma. Despite this, the molecular events that influence NASH pathogenesis remain poorly understood. The objectives of the current study are to delineate the transcriptomic and proteomic signatures of NASH liver, to identify potential pathogenic pathways and factors, and to critically assess their role in NASH pathogenesis. Methods We performed RNA sequencing and quantitative proteomic analyses on the livers from healthy and diet-induced NASH mice. We examined the association between plasma levels of TSK, a newly discovered hepatokine, and NASH pathologies and reversal in response to dietary switch in mice. Using TSK knockout mouse model, we determined how TSK deficiency modulates key aspects of NASH pathogenesis. Results RNA sequencing and quantitative proteomic analyses revealed that diet-induced NASH triggers concordant reprogramming of the liver transcriptome and proteome in mice. NASH pathogenesis is linked to elevated plasma levels of the hepatokine TSK, whereas dietary switch reverses NASH pathologies and reduces circulating TSK concentrations. Finally, TSK inactivation protects mice from diet-induced NASH and liver transcriptome remodeling. Conclusions Global transcriptomic and proteomic profiling of healthy and NASH livers revealed the molecular signatures of diet-induced NASH and dysregulation of the liver secretome. Our study illustrates a novel pathogenic mechanism through which elevated TSK in circulation promotes NASH pathologies, thereby revealing a potential target for therapeutic intervention., Highlights • NASH triggers concordant reprogramming of the liver transcriptome and proteome. • NASH pathogenesis is linked to elevated plasma levels of the hepatokine TSK. • Dietary switch reverses NASH pathologies and reduces plasma TSK levels. • TSK inactivation protects mice from diet-induced NASH and liver transcriptome remodeling.

Heparan sulfate (HS), a highly sulfated linear polysaccharide, is involved in diverse biological functions in various tissues. Although previous studies have suggested a possible contribution of HS to the differentiation of white adipocytes, there has been no direct evidence supporting this. Here, we inhibited the synthesis of HS chains in 3T3-L1 cells using CRISPR–Cas9 technology, resulting in impaired differentiation of adipocytes with attenuated bone morphogenetic protein 4 (BMP4)–fibroblast growth factor 1 (FGF1) signaling pathways. HS reduction resulted in reduced glucose uptake and decreased insulin-dependent intracellular signaling. We then made heterozygous mutant mice for the Ext1 gene, which encodes an enzyme essential for the HS biosynthesis, specifically in the visceral white adipose tissue (Fabp4-Cre+::Ext1flox/WT mice, hereafter called Ext1Δ/WT) to confirm the importance of HS in vivo. The expression levels of transcription factors that control adipocyte differentiation, such as peroxisome proliferator–activated receptor gamma, were reduced in Ext1Δ/WT adipocytes, which contained smaller, unilocular lipid droplets, reduced levels of enzymes involved in lipid synthesis, and altered expression of BMP4–FGF1 signaling molecules. Furthermore, we examined the impact of HS reduction in visceral white adipose tissue on systemic glucose homeostasis. We observed that Ext1Δ/WT mice showed glucose intolerance because of insulin resistance. Our results demonstrate that HS plays a crucial role in the differentiation of white adipocytes through BMP4–FGF1 signaling pathways, thereby contributing to insulin sensitivity and glucose homeostasis.

Background Excess visceral fat (VF) or high body mass index (BMI) is risk factors for severe COVID-19. The receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is expressed at higher levels in the VF than in the subcutaneous fat (SCF) of obese patients. Aim To show that visceral fat accumulation better predicts severity of COVID-19 outcome compared to either SCF amounts or BMI. Methods We selected patients with symptomatic COVID-19 and a computed tomography (CT) scan. Severe COVID-19 was defined as requirement for mechanical ventilation or death. Fat depots were quantified on abdominal CT scan slices and the measurements were correlated with the clinical outcomes. ACE 2 mRNA levels were quantified in fat depots of a separate group of non-COVID-19 subjects using RT-qPCR. Results Among 165 patients with a mean BMI of 26.1 ± 5.4 kg/m2, VF was associated with severe COVID-19 (p = 0.022) and SCF was not (p = 0.640). Subcutaneous fat was not different in patients with mild or severe COVID-19 and the SCF/VF ratio was lower in patients with severe COVID-19 (p = 0.010). The best predictive value for severe COVID-19 was found for a VF area ≥128.5 cm2 (ROC curve), which was independently associated with COVID-19 severity (p, Highlights • Visceral fat is associated with COVID-19 severity in Caucasian adults. • The expression of angiotensin converting enzyme type 2, the receptor of SARS-Cov2, in visceral fat may contribute to the cytokine storm. • Metabolic health of patients with COVID-19 should be carefully evaluated.

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous lipids with antidiabetic and anti-inflammatory effects. Each FAHFA family consists of esters with different acyl chains and multiple isomers with branch points at different carbons. Some FAHFAs, including palmitic acid hydroxy stearic acids (PAHSAs), improve insulin sensitivity and glucose tolerance in mice by enhancing glucose-stimulated insulin secretion (GSIS), insulin-stimulated glucose transport, and insulin action to suppress hepatic glucose production and reducing adipose tissue inflammation. However, little is known about the biological effects of other FAHFAs. Here, we investigated whether PAHSAs, oleic acid hydroxy stearic acid, palmitoleic acid hydroxy stearic acid, and stearic acid hydroxy stearic acid potentiate GSIS in β-cells and human islets, insulin-stimulated glucose uptake in adipocytes, and anti-inflammatory effects in immune cells. We also investigated whether they activate G protein–coupled receptor 40, which mediates the effects of PAHSAs on insulin secretion and sensitivity in vivo. We show that many FAHFAs potentiate GSIS, activate G protein–coupled receptor 40, and attenuate LPS-induced chemokine and cytokine expression and secretion and phagocytosis in immune cells. However, fewer FAHFAs augment insulin-stimulated glucose uptake in adipocytes. S-9-PAHSA, but not R-9-PAHSA, potentiated GSIS and glucose uptake, while both stereoisomers had anti-inflammatory effects. FAHFAs containing unsaturated acyl chains with higher branching from the carboxylate head group are more likely to potentiate GSIS, whereas FAHFAs with lower branching are more likely to be anti-inflammatory. This study provides insight into the specificity of the biological actions of different FAHFAs and could lead to the development of FAHFAs to treat metabolic and immune-mediated diseases.

Objective Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state. Methods Protein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130Δadipo) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modeled in vitro by exposing mature adipocytes to isoproterenol after stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively. Results Inguinal WAT of HFD-fed gp130Δadipo mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro, treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. As with mouse data, OSM gene expression in human WAT positively correlated with BMI (r = 0.284, p = 0.021, n = 66) and negatively with UCP1 expression (r = −0.413, p, Graphical abstract Image 1, Highlights • OSM is regulated under obesity and negatively correlates with UCP1 in WAT. • OSM suppresses isoproterenol-induced UCP1 in subcutaneous adipocytes. • OSM signals through the gp130-STAT3 pathway to lower UCP1 expression. • Obese mice lacking gp130 in adipocytes exhibit increased WAT browning.

The liver is the central organ regulating cholesterol synthesis, storage, transport, and elimination. Mouse carboxylesterase 1d (Ces1d) and its human ortholog CES1 have been described to possess lipase activity and play roles in hepatic triacylglycerol metabolism and VLDL assembly. It has been proposed that Ces1d/CES1 might also catalyze cholesteryl ester (CE) hydrolysis in the liver and thus be responsible for the hydrolysis of HDL-derived CE; this could contribute to the final step in the reverse cholesterol transport (RCT) pathway, wherein cholesterol is secreted from the liver into bile and feces, either directly or after conversion to water-soluble bile salts. However, the proposed function of Ces1d/CES1 as a CE hydrolase is controversial. In this study, we interrogated the role hepatic Ces1d plays in cholesterol homeostasis using liver-specific Ces1d-deficient mice. We rationalized that if Ces1d is a major hepatic CE hydrolase, its absence would (1) reduce in vivo RCT flux and (2) provoke liver CE accumulation after a high-cholesterol diet challenge. We found that liver-specific Ces1d-deficient mice did not show any difference in the flux of in vivo HDL-to-feces RCT nor did it cause additional liver CE accumulation after high-fat, high-cholesterol Western-type diet feeding. These findings challenge the importance of Ces1d as a major hepatic CE hydrolase.

Cyclic AMP-responsive element-binding protein H (CREBH encoded by Creb3l3) is a transcription factor that regulates the expression of genes that control lipid and glucose metabolism as well as inflammation. CREBH is upregulated in the liver under conditions of overnutrition, and mice globally lacking the gene (CREBH-/-) are highly susceptible to diet-induced obesity, insulin resistance, and hepatic steatosis. The net protective effects of CREBH have been attributed in large part to the activities of fibroblast growth factor (Fgf)-21 (Fgf21), a target gene that promotes weight loss, improves glucose homeostasis, and reduces hepatic lipid accumulation. To explore the possibility that activation of the CREBH–Fgf21 axis could ameliorate established effects of high-fat feeding, we generated an inducible transgenic hepatocyte-specific CREBH overexpression mouse model (Tg-rtTA). Acute overexpression of CREBH in livers of Tg-rtTA mice effectively reversed diet-induced obesity, insulin resistance, and hepatic steatosis. These changes were associated with increased activities of thermogenic brown and beige adipose tissues in Tg-rtTA mice, leading to reductions in fat mass, along with enhanced insulin sensitivity and glucose tolerance. Genetically silencing Fgf21 in Tg-rtTA mice abrogated the CREBH-mediated reductions in body weight loss, but only partially reversed the observed improvements in glucose metabolism. These findings reveal that the protective effects of CREBH activation may be leveraged to mitigate diet-induced obesity and associated metabolic abnormalities in both Fgf21-dependent and Fgf21-independent pathways.

Objective Canonical Wnt/β-catenin signaling is a well-studied endogenous regulator of mesenchymal cell fate determination, promoting osteoblastogenesis and inhibiting adipogenesis. However, emerging genetic evidence in humans links a number of Wnt pathway members to body fat distribution, obesity, and metabolic dysfunction, suggesting that this pathway also functions in adipocytes. Recent studies in mice have uncovered compelling evidence that the Wnt signaling pathway plays important roles in adipocyte metabolism, particularly under obesogenic conditions. However, complexities in Wnt signaling and differences in experimental models and approaches have thus far limited our understanding of its specific roles in this context. Methods To investigate roles of the canonical Wnt pathway in the regulation of adipocyte metabolism, we generated adipocyte-specific β-catenin (β-cat) knockout mouse and cultured cell models. We used RNA sequencing, ChIP sequencing, and molecular approaches to assess expression of Wnt targets and lipogenic genes. We then used functional assays to evaluate effects of β-catenin deficiency on adipocyte metabolism, including lipid and carbohydrate handling. In mice maintained on normal chow and high-fat diets, we assessed the cellular and functional consequences of adipocyte-specific β-catenin deletion on adipose tissues and systemic metabolism. Results We report that in adipocytes, the canonical Wnt/β-catenin pathway regulates de novo lipogenesis (DNL) and fatty acid monounsaturation. Further, β-catenin mediates effects of Wnt signaling on lipid metabolism in part by transcriptional regulation of Mlxipl and Srebf1. Intriguingly, adipocyte-specific loss of β-catenin is sensed and defended by CD45-/CD31- stromal cells to maintain tissue-wide Wnt signaling homeostasis in chow-fed mice. With long-term high-fat diet, this compensatory mechanism is overridden, revealing that β-catenin deletion promotes resistance to diet-induced obesity and adipocyte hypertrophy and subsequent protection from metabolic dysfunction. Conclusions Taken together, our studies demonstrate that Wnt signaling in adipocytes is required for lipogenic gene expression, de novo lipogenesis, and lipid desaturation. In addition, adipose tissues rigorously defend Wnt signaling homeostasis under standard nutritional conditions, such that stromal-vascular cells sense and compensate for adipocyte-specific loss. These findings underscore the critical importance of this pathway in adipocyte lipid metabolism and adipose tissue function., Graphical abstract Image 1, Highlights • Wnt/β-catenin signaling regulates lipogenesis and lipid unsaturation in adipocytes. • Effects on lipogenesis are mediated in part by the regulation of Mlxipl and Srebf1. • Loss of adipocyte β-catenin is defended by CD45-/CD31- cells in chow-fed mice. • β-cat−/− mice are protected from diet-induced obesity and metabolic dysfunction.

Adipose tissues, including white, beige, and brown adipose tissue, have evolved to be highly dynamic organs. Adipose tissues undergo profound changes during development and regeneration and readily undergo remodeling to meet the demands of an everchanging metabolic landscape. The dynamics are determined by the high plasticity of adipose tissues, which contain various cell types: adipocytes, immune cells, endothelial cells, nerves, and fibroblasts. There are numerous proteins that participate in regulating the plasticity of adipose tissues. Among these, bone morphogenetic proteins (BMPs) were initially found to regulate the differentiation of adipocytes, and they are being reported to have pleiotropic functions by emerging studies. Here, in the first half of the article, we summarize the plasticity of adipocytes and macrophages, which are two groups of cells targeted by BMP signaling in adipose tissues. We then review how BMPs regulate the differentiation, death, and lipid metabolism of adipocytes. In addition, the potential role of BMPs in regulating adipose tissue macrophages is considered. Finally, the expression of BMPs in adipose tissues and their metabolic relevance are discussed.

Obesity is regarded as an abnormal expansion and excessive accumulation of fat mass in white adipose tissue. The involvement of oxidative stress in the development of obesity is still unclear. Although mainly present in peroxisomes, catalase scavenges intracellular H2O2 at toxic levels. Therefore, we used catalase-knockout (CKO) mice to elucidate the involvement of excessive H2O2 in the development of obesity. CKO mice with C57BL/6J background gained more weight with higher body fat mass with age than age-matched wild-type (WT) mice fed with either chow or high-fat diets. This phenomenon was attenuated by concomitant treatment with the antioxidants, melatonin or N-acetyl cysteine. Moreover, CKO mouse embryonic fibroblasts (MEFs) appeared to differentiate to adipocytes more easily than WT MEFs, showing increased H2O2 concentrations. Using 3T3-L1-derived adipocytes transfected with catalase-small interfering RNA, we confirmed that a more prominent lipogenesis occurred in catalase-deficient cells than in WT cells. Catalase-deficient adipocytes presented increased nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression but decreased adenosine monophosphate-activated protein kinase (AMPK) expression. Treatment with a NOX4 inhibitor or AMPK activator rescued the propensity for obesity of CKO mice. These findings suggest that excessive H2O2 and related oxidative stress increase body fat mass via both adipogenesis and lipogenesis. Manipulating NOX4 and AMPK in white adipocytes may be a therapeutic tool against obesity augmented by oxidative stress., Graphical abstract Image 1, Highlights • Catalase deficiency facilitates both adipogenesis and adipocyte hypertrophy. • Catalase deficiency activates NOX4, resulting in further oxidative stress increase. • Catalase KO-induced HIF1α activation and pentose phosphate pathway further activate NOX4. • Catalase deficiency inhibits AMPKα, which is attributed to mitochondrial dysfunction. • Antioxidants, NOX4 inhibitors, and AMPKα activators prevent obesity.

Objective Studies in mice have shown that the decrease in lipoprotein lipase (LPL) activity in adipose tissue upon fasting is mediated by induction of the inhibitor ANGPTL4. Here, we aimed to validate this concept in humans by determining the effect of a prolonged fast on ANGPTL4 and LPL gene and protein expression in human subcutaneous adipose tissue. Methods Twenty-three volunteers ate a standardized meal at 18.00 h and fasted until 20.00 h the next day. Blood was drawn and periumbilical adipose tissue biopsies were collected 2 h and 26 h after the meal. Results Consistent with previous mouse data, LPL activity in human adipose tissue was significantly decreased by fasting (−60%), concurrent with increased ANGPTL4 mRNA (+90%) and decreased ANGPTL8 mRNA (−94%). ANGPTL4 protein levels in adipose tissue were also significantly increased by fasting (+46%), whereas LPL mRNA and protein levels remained unchanged. In agreement with the adipose tissue data, plasma ANGPTL4 levels increased upon fasting (+100%), whereas plasma ANGPTL8 decreased (−79%). Insulin, levels of which significantly decreased upon fasting, downregulated ANGPTL4 mRNA and protein in primary human adipocytes. By contrast, cortisol, levels of which significantly increased upon fasting, upregulated ANGPTL4 mRNA and protein in primary human adipocytes as did fatty acids. Conclusion ANGPTL4 levels in human adipose tissue are increased by fasting, likely via increased plasma cortisol and free fatty acids and decreased plasma insulin, resulting in decreased LPL activity. This clinical trial was registered with identifier NCT03757767., Highlights • 24-h fast in humans reduces LPL activity in subcutaneous adipose tissue. • 24-h fast in humans increases adipose ANGPTL4 mRNA, protein, and plasma ANGPTL4 levels. • Cortisol, fatty acids, and insulin regulate ANGPTL4 in vitro. • ANGPTL4 mediates the reduction in adipose LPL activity during fasting. • 24-h fast in humans decreases adipose ANGPTL8 mRNA and plasma ANGPTL8 levels.

Objective Obesity is a key risk factor for many secondary chronic illnesses, including type 2 diabetes and cardiovascular disease. Canonical Wnt/β-catenin signaling is established as an important endogenous inhibitor of adipogenesis. This pathway is operative in mature adipocytes; however, its roles in this context remain unclear due to complexities of Wnt signaling and differences in experimental models. In this study, we used novel cultured cell and mouse models to investigate functional roles of Wnts secreted from adipocytes. Methods We generated adipocyte-specific Wntless (Wls) knockout mice and cultured cell models to investigate molecular and metabolic consequences of disrupting Wnt secretion from mature adipocytes. To characterize Wls-deficient cultured adipocytes, we evaluated the expression of Wnt target and lipogenic genes and the downstream functional effects on carbohydrate and lipid metabolism. We also investigated the impact of adipocyte-specific Wls deletion on adipose tissues and global glucose metabolism in mice fed normal chow or high-fat diets. Results Many aspects of the Wnt signaling apparatus are expressed and operative in mature adipocytes, including the Wnt chaperone Wntless. Deletion of Wntless in cultured adipocytes results in the inhibition of de novo lipogenesis and lipid monounsaturation, likely through repression of Srebf1 (SREBP1c) and Mlxipl (ChREBP) and impaired cleavage of immature SREBP1c into its active form. Adipocyte-specific Wls knockout mice (Wls-/-) have lipogenic gene expression in adipose tissues and isolated adipocytes similar to that of controls when fed a normal chow diet. However, closer investigation reveals that a subset of Wnts and downstream signaling targets are upregulated within stromal-vascular cells of Wls-/- mice, suggesting that adipose tissues defend loss of Wnt secretion from adipocytes. Interestingly, this compensation is lost with long-term high-fat diet challenges. Thus, after six months of a high-fat diet, Wls-/- mice are characterized by decreased adipocyte lipogenic gene expression, reduced visceral adiposity, and improved glucose homeostasis. Conclusions Taken together, these studies demonstrate that adipocyte-derived Wnts regulate de novo lipogenesis and lipid desaturation and coordinate the expression of lipogenic genes in adipose tissues. In addition, we report that Wnt signaling within adipose tissues is defended, such that a loss of Wnt secretion from adipocytes is sensed and compensated for by neighboring stromal-vascular cells. With chronic overnutrition, this compensatory mechanism is lost, revealing that Wls-/- mice are resistant to diet-induced obesity, adipocyte hypertrophy, and metabolic dysfunction., Graphical abstract Image 1, Highlights • Wntless in adipocytes is required for the expression of a network of lipogenic genes. • Regulation of lipogenic genes by Wntless is likely mediated by Srebf1 and Mlxipl. • Adipose tissues defend loss of adipocyte-derived Wnt secretion. • Compensation for Wntless deficiency is lost with diet-induced obesity. • Wntless deficiency causes reduced adipocyte size and improved metabolic function.

DNA methylation regulates gene transcription and is involved in various physiological processes in mammals, including development and hematopoiesis. It is catalyzed by DNA methyltransferases including Dnmt1, Dnmt3a, and Dnmt3b. For Dnmt3b, its effects on transcription can result from its own DNA methylase activity, the recruitment of other Dnmts to mediate methylation, or transcription repression in a methylation-independent manner. Low-frequency mutations in human DNMT3B are found in hematologic malignancies including cutaneous T-cell lymphomas, hairy cell leukemia, and diffuse large B-cell lymphomas. Moreover, Dnmt3b is a tumor suppressor in oncogene-driven lymphoid and myeloid malignancies in mice. However, it is poorly understood how the different Dnmt3b activities contribute to these outcomes. We modulated Dnmt3b activity in vivo by generating Dnmt3b+/− mice expressing one wild-type allele as well as Dnmt3b+/CI and Dnmt3bCI/CI mice where one or both alleles express catalytically inactive Dnmt3bCI. We show that 43% of Dnmt3b+/− mice developed T-cell lymphomas, chronic lymphocytic leukemia, and myeloproliferation over 18 months, thus resembling phenotypes previously observed in Dnmt3a+/− mice, possibly through regulation of shared target genes. Interestingly, Dnmt3b+/CI and Dnmt3bCI/CI mice survived postnatal development and were affected by B-cell rather than T-cell malignancies with decreased penetrance. Genome-wide hypomethylation, increased expression of oncogenes such as Jdp2, STAT1, and Trip13, and p53 downregulation were major events contributing to Dnmt3b+/− lymphoma development. We conclude that Dnmt3b catalytic activity is critical to prevent B-cell transformation in vivo, whereas accessory and methylation-independent repressive functions are important to prevent T-cell transformation.

It is becoming obvious that in addition to aging and various hearth pathologies, excess of body weight, especially obesity is a major risk factor for severity of COVID-19 infection. Intriguingly the receptor for SARS-CoV-2 is ACE2, a member of the angiotensin receptor family that has a relatively large tissue distribution. This observation likely explains the multitude of symptoms that have been described from human patients. The adipose tissue also expresses ACE2, suggesting that adipocytes are potentially infected by SARS-CoV-2. Here we discuss some of the potential contribution of the adipose tissue to the severity of the infection and propose some aspects of obese patients metabolic phenotyping to help stratification of individuals with high risk of severe disease., Highlights • Adipose tissue may be a reservoir for SARS-CoV-2 production. • Obesity-induced chronic inflammatory status generates inappropriate immune response. • Exaggerated-adipose tissue lipolysis in response to proinflammatory cytokines might exert additional lipotoxic effects. • Potential role of adipose-derived products in aggravating COVID-19 infection. • Adipose tissue contribution to COVID-19 severity through the perturbation of local renin angiotensin system.

Obesity associates with inflammation, insulin resistance and higher blood lipids. It is unclear if immune responses facilitate lipolysis separate from hormone or adrenergic signals. We found that an ancient component of ER stress, inositol-requiring protein 1 (IRE1), discriminates inflammation-induced adipocyte lipolysis versus lipolysis regulated by adrenergic or hormonal stimuli. Inhibiting IRE1 kinase activity was sufficient to block adipocyte-autonomous lipolysis from multiple inflammatory ligands, including bacterial components, certain cytokines, and thapsigargin-induced ER stress. Adipocyte-specific deletion of IRE1 in mice prevented inflammatory ligand-induced lipolysis in adipose tissue. IRE1 kinase activity was dispensable for isoproterenol and cAMP-induced lipolysis in adipocytes and mouse adipose tissue. IRE1 RNase activity was not associated with inflammation-induced adipocyte lipolysis. We found no role for canonical unfolded protein responses (UPR) or ABL kinases in linking ER stress to lipolysis. Lipolysis was unchanged in adipose tissue from GRP78/BiP+/- compared to littermate mice. Tyrosine kinase inhibitors (TKIs) such as imatinib, which reduce ER stress and IRE1 RNase activity, did not alter lipolysis from inflammatory stimuli. Inhibiting IRE1 kinase activity blocked adipocyte NF-κB activation and Interleukin-6 (Il6) production due to inflammatory ligands. Inflammation-induced lipolysis mediated by IRE1 occurred independently from changes in insulin signalling in adipocytes. Therefore, inflammation can promote IRE1-mediated lipolysis independent of adipocyte insulin resistance. Our results show that IRE1 propagates an inflammation-specific lipolytic program independent from hormonal or adrenergic regulation, including insulin resistance. Targeting IRE1 kinase activity may benefit metabolic syndrome and inflammatory lipid disorders.SignificanceAdipocytes maintain metabolic homeostasis by storing nutrients and releasing lipids into the blood via lipolysis. Catecholamines stimulate adrenergic-mediated lipolysis, whereas insulin inhibits lipolysis. Obesity is associated with elevated blood lipids and inflammation, which can impair insulin-mediated suppression of lipolysis (i.e. insulin resistance). It is unclear if inflammatory triggers of lipolysis require insulin resistance or if specific lipolytic triggers engage distinct cell stress components. We found that a specific ER stress response was required for inflammation-mediated lipolysis, not adrenergic-mediated lipolysis. Bacterial and cytokine-induced lipolysis required adipocyte IRE1 kinase activity, but not IRE1 RNase activity typical of the ER stress-related unfolded protein response. We propose that inflammatory triggers of lipolysis engage IRE1 kinase independent of catecholamine and hormone responses, including insulin resistance.Graphical AbstractIRE1 kinase activity promotes an inflammation-specific adipocyte lipolytic program that is separate from hormonal or adrenergic regulation of lipolysis.

Objective Peroxisome proliferator-activated receptors (PPARs) are key transcription factors that regulate adipose development and function, and the conversion of white into brown-like adipocytes. Here we investigated whether PPARα and PPARγ activation synergize to induce the browning of white fat. Methods A selection of PPAR activators was tested for their ability to induce the browning of both mouse and human white adipocytes in vitro, and in vivo in lean and obese mice. Results All dual PPARα/γ activators tested robustly increased uncoupling protein 1 (Ucp1) expression in both mouse and human adipocytes in vitro, with tesaglitazar leading to the largest Ucp1 induction. Importantly, dual PPARα/γ activator tesaglitazar strongly induced browning of white fat in vivo in both lean and obese male mice at thermoneutrality, greatly exceeding the increase in Ucp1 observed with the selective PPARγ activator rosiglitazone. While selective PPARγ activation was sufficient for the conversion of white into brown-like adipocytes in vitro, dual PPARα/γ activation was superior to selective PPARγ activation at inducing white fat browning in vivo. Mechanistically, the superiority of dual PPARα/γ activators is mediated at least in part via a PPARα-driven increase in fibroblast growth factor 21 (FGF21). Combined treatment with rosiglitazone and FGF21 resulted in a synergistic increase in Ucp1 mRNA levels both in vitro and in vivo. Tesaglitazar-induced browning was associated with increased energy expenditure, enhanced insulin sensitivity, reduced liver steatosis, and an overall improved metabolic profile compared to rosiglitazone and vehicle control groups. Conclusions PPARγ and PPARα synergize to induce robust browning of white fat in vivo, via PPARγ activation in adipose, and PPARα-mediated increase in FGF21., Graphical abstract Dual PPARα/γ activation is superior to selective PPARγ activation at inducing browning of white fat in vivo: via PPARγ action in the adipose and a PPARα-mediated action in the liver resulting in increased circulating fibroblast growth factor 21 (FGF21).Image 1, Highlights • Dual PPARα/γ activators robustly induce browning of white fat in vitro and in vivo. • PPARγ action alone is sufficient to convert white into brown-like adipocytes in vitro. • Dual PPARα/γ activators are superior to PPARγ activators for browning of white fat in vivo. • PPARγ action in adipose and PPARα-mediated increase in FGF21 synergize to induce browning of white fat in vivo.

Background and aim Metabolic disturbances are known for their increasing epidemiological importance. Ilex paraguariensis presents a potential option for mitigating lipid metabolism imbalance. However, most of the literature to date has not considered sex bias. This study aimed to evaluate the effect of Ilex paraguariensis on the metabolism of different adipose tissue depots in males and females. Experimental procedure After ovariectomy, female Wistar rats received daily treatment with the extract (1 g/kg) for forty-five days. Biochemical serum parameters and tissue metabolism were evaluated. Oxidation, lipogenesis and lipolysis were evaluated in brown, white visceral, retroperitoneal and gonadal adipose tissues. Results and conclusion The results showed that treatment with the extract led to a reduced weight gain in ovariectomised females in comparison to control. The triglyceride concentration was decreased in males. Glucose oxidation and lipid synthesis in visceral and retroperitoneal adipose tissues were restored in ovariectomised females after treatment. The response to epinephrine decreased in visceral adipose tissue of control males; however, lipolysis in females did not respond to ovariectomy or treatment. These findings highlight the enormous potential effects of I. paraguariensis on lipid metabolism, modulating lipogenic pathways in females and lipolytic pathways in males. Furthermore, the sex approach applied in this study contributes to more effective screening of the effects of I. paraguariensis bioactive substances., Graphical abstract Image 1, Highlights • Ilex paraguariensis reduced weight gain of ovariectomy females to control levels • Serum triglycerides decreased in male and estrogen-deficient female after treatment • Treatment restored glucose oxidation and lipogenesis of estrogen-deficient females • I. paraguariensis decreased lipolysis response in visceral adipose tissue of males

Objective Physical exercise training is associated with increased glucose uptake in skeletal muscle and improved glycemic control. HDAC5, a class IIa histone deacetylase, has been shown to regulate transcription of the insulin-responsive glucose transporter GLUT4 in cultured muscle cells. In this study, we analyzed the contribution of HDAC5 to the transcriptional network in muscle and the beneficial effect of muscle contraction and regular exercise on glucose metabolism. Methods HDAC5 knockout mice (KO) and wild-type (WT) littermates were trained for 8 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls. Hdac5-deficient skeletal muscle and cultured Hdac5-knockdown (KD) C2C12 myotubes were utilized for studies of gene expression and glucose metabolism. Chromatin immunoprecipitation (ChIP) studies were conducted to analyze Il6 promoter activity using H3K9ac and HDAC5 antibodies. Results Global transcriptome analysis of Hdac5 KO gastrocnemius muscle demonstrated activation of the IL-6 signaling pathway. Accordingly, knockdown of Hdac5 in C2C12 myotubes led to higher expression and secretion of IL-6 with enhanced insulin-stimulated activation of AKT that was reversed by Il6 knockdown. Moreover, Hdac5-deficient myotubes exhibited enhanced glucose uptake, glycogen synthesis, and elevated expression levels of the glucose transporter GLUT4. Transcription of Il6 was further enhanced by electrical pulse stimulation in Hdac5-deficient C2C12 myotubes. ChIP identified a ∼1 kb fragment of the Il6 promoter that interacts with HDAC5 and demonstrated increased activation-associated histone marker AcH3K9 in Hdac5-deficient muscle cells. Exercise intervention of HDAC5 KO mice resulted in improved systemic glucose tolerance as compared to WT controls. Conclusions We identified HDAC5 as a negative epigenetic regulator of IL-6 synthesis and release in skeletal muscle. HDAC5 may exert beneficial effects through two different mechanisms, transcriptional control of genes required for glucose disposal and utilization, and HDAC5-dependent IL-6 signaling cross-talk to improve glucose uptake in muscle in response to exercise.

Objective Increasing energy expenditure through activation of brown adipose tissue (BAT) thermogenesis is an attractive approach to counteract obesity. It is therefore essential to understand the molecular mechanisms that control BAT functions. Until now several members of the Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway have been implicated as being relevant for BAT physiology. However, whether the STAT family member STAT5 is important for the thermogenic property of adipose tissues is unknown. Therefore, we have investigated the role of STAT5 in thermogenic fat in this paper. Methods We performed metabolic and molecular analyses using mice that harbor an adipocyte-specific deletion of Stat5a/b alleles. Results We found that STAT5 is necessary for acute cold-induced temperature maintenance and the induction of lipid mobilization in BAT following β3-adrenergic stimulation. Moreover, mitochondrial respiration of primary differentiated brown adipocytes lacking STAT5 was diminished. Increased sensitivity to cold stress upon STAT5 deficiency was associated with reduced expression of thermogenic markers including uncoupling protein 1 (UCP1), while decreased stimulated lipolysis was linked to decreased protein kinase A (PKA) activity. Additionally, brown remodeling of white adipose tissue was diminished following chronic β3-adrenergic stimulation, which was accompanied by a decrease in mitochondrial performance. Conclusion We conclude that STAT5 is essential for the functionality and the β-adrenergic responsiveness of thermogenic adipose tissue., Highlights • Impaired temperature maintenance in mice deficient in adipocyte STAT5 after acute cold exposure. • Blocked β3-adrenergic induction of lipolysis and PKA activity in BAT upon STAT5 deficiency. • Reduced respiratory capacity in primary differentiated brown adipocytes lacking STAT5. • Diminished brown remodeling of STAT5 deficient ScWAT after chronic β3-adrenergic stimulation.

The diversity of glycerophospholipid species in cellular membranes is immense and affects various biological functions. Glycerol-3-phosphate acyltransferases (GPATs) and lysophospholipid acyltransferases (LPLATs), in concert with phospholipase A1/2s enzymes, contribute to this diversity via selective esterification of fatty acyl chains at the sn-1 or sn-2 positions of membrane phospholipids. These enzymes are conserved across all kingdoms, and in mammals four GPATs of the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) family and at least 14 LPLATs, either of the AGPAT or the membrane-bound O-acyltransferase (MBOAT) families, have been identified. Here we provide an overview of the biochemical and biological activities of these mammalian enzymes, including their predicted structures, involvements in human diseases, and essential physiological roles as revealed by gene-deficient mice. Recently, the nomenclature used to refer to these enzymes has generated some confusion due to the use of multiple names to refer to the same enzyme and instances of the same name being used to refer to completely different enzymes. Thus, this review proposes a more uniform LPLAT enzyme nomenclature, as well as providing an update of recent advances made in the study of LPLATs, continuing from our JBC mini review in 2009.

Aberrant fatty acid (FA) metabolism is a hallmark of proliferating cells, including untransformed fibroblasts or cancer cells. Lipolysis of intracellular triglyceride (TG) stores by adipose triglyceride lipase (ATGL) provides an important source of FAs serving as energy substrates, signaling molecules, and precursors for membrane lipids. To investigate if ATGL-mediated lipolysis impacts cell proliferation, we modified ATGL activity in murine embryonic fibroblasts (MEFs) and in five different cancer cell lines to determine the consequences on cell growth and metabolism. Genetic or pharmacological inhibition of ATGL in MEFs causes impaired FA oxidation, decreased ROS production, and a substrate switch from FA to glucose leading to decreased AMPK-mTOR signaling and higher cell proliferation rates. ATGL expression in these cancer cells is low when compared to MEFs. Additional ATGL knockdown in cancer cells did not significantly affect cellular lipid metabolism or cell proliferation whereas the ectopic overexpression of ATGL increased lipolysis and reduced proliferation. In contrast to ATGL silencing, pharmacological inhibition of ATGL by Atglistatin© impeded the proliferation of diverse cancer cell lines, which points at an ATGL-independent effect. Our data indicate a crucial role of ATGL-mediated lipolysis in the regulation of cell proliferation. The observed low ATGL activity in cancer cells may represent an evolutionary selection process and mechanism to sustain high cell proliferation rates. As the increasing ATGL activity decelerates proliferation of five different cancer cell lines this may represent a novel therapeutic strategy to counteract uncontrolled cell growth., Highlights • ATGL deficiency increases cell proliferation and decreases phosphorylation of AMPK in murine embryonic fibroblasts. • ATGL silencing does not reduce lipolysis or increase proliferation of diverse cancer cells. • Increasing ATGL activity represses cell proliferation in a panel of cancer cells. • Atglistatin© exhibits an ATGL independent tumor suppressive effect.

Objective Beyond the taste buds, sweet taste receptors (STRs; T1R2/T1R3) are also expressed on enteroendocrine cells, where they regulate gut peptide secretion but their regulatory function within the intestine is largely unknown. Methods Using T1R2-knock out (KO) mice we evaluated the role of STRs in the regulation of glucose absorption in vivo and in intact intestinal preparations ex vivo. Results STR signaling enhances the rate of intestinal glucose absorption specifically in response to the ingestion of a glucose-rich meal. These effects were mediated specifically by the regulation of GLUT2 transporter trafficking to the apical membrane of enterocytes. GLUT2 translocation and glucose transport was dependent and specific to glucagon-like peptide 2 (GLP-2) secretion and subsequent intestinal neuronal activation. Finally, high-sucrose feeding in wild-type mice induced rapid downregulation of STRs in the gut, leading to reduced glucose absorption. Conclusions Our studies demonstrate that STRs have evolved to modulate glucose absorption via the regulation of its transport and to prevent the development of exacerbated hyperglycemia due to the ingestion of high levels of sugars., Highlights • The intestinal T1R2 receptor enhances glucose absorption in vivo and ex vivo. • Pharmacological inhibition of STRs reduces glucose flux in human intestinal preparations. • T1R2 regulates glucose absorption dependent on GLUT2 activity in enterocytes. • GLP-2 mediates the effects of T1R2 signaling through activation of enteric neurons. • High sucrose diet rapidly downregulates STRs leading to reduced glucose absorption.

Objective The potential for brown adipose tissue (BAT) to be targeted as a therapeutic option to combat obesity has been heightened by the discovery of a brown–like form of inducible “beige” adipose tissue in white fat which has overlapping structural and functional properties to “classical” BAT. The likelihood that both beige and brown fat are recruited functionally by neural mechanisms, taken together with the lack of a detailed understanding of the nature of changes in the nervous system when white adipose tissue (WAT) is transformed to brown, provides the impetus for this study. Here, we aim to identify whether there is a shift in the gene expression profile in neurons directly innervating inguinal white adipose tissue (iWAT) that has undergone “beiging” to a signature that is more similar to neurons projecting to BAT. Methods Two groups of rats, one housed at thermoneutrality (27 °C) and the other exposed to cold (8 °C) for 7 days, were killed, and their T13/L1 ganglia, stellate ganglion (T1/T2), or superior cervical ganglion (SCG, C2/3) removed. This approach yielded ganglia containing neurons that innervate either beiged white fat (8 °C for 7 days), inguinal WAT (27 °C for 7 days), BAT (both 27 °C and 8 °C for 7 days) or non-WAT (8 °C for 7 days), the latter included to isolate changes in gene expression that were more aligned with a response to cold exposure than the transformation of white to beige adipocytes. Bioinformatics analyses of RNA sequencing data was performed followed by Ingenuity Pathway Analysis (IPA) to determine differential gene expression and recruitment of biosynthetic pathways. Results When iWAT is “beiged” there is a significant shift in the gene expression profile of neurons in sympathetic ganglia (T13/L1) innervating this depot toward a gene neurochemical signature that is similar to the stellate ganglion projecting to BAT. Bioinformatics analyses of “beiging” related genes revealed upregulation of genes encoding neuropeptides proopiomelanocortin (POMC) and calcitonin-gene related peptide (CGRP) within ganglionic neurons. Treatment of differentiated 3T3L1 adipocytes with αMSH, one of the products cleaved from POMC, results in an elevation in lipolysis and the beiging of these cells as indicated by changes in gene expression markers of browning (Ucp1 and Ppargc1a). Conclusion These data indicate that, coincident with beiging, there is a shift toward a “brown-like” neurochemical signature of postganglionic neurons projecting to inguinal white fat, an increased expression of POMC, and, consistent with a causative role for this prohormone in beiging, an αMSH-mediated increase in beige gene markers in isolated adipocytes., Graphical abstract, Highlights • RNA Seq showed shifts in neuronal gene expression following browning of white fat. • Gene expression in ganglia projecting to white fat became brown-like with beiging. • Bioinformatics analyses revealed neuronal gene candidates associated with beiging. • Prominent gene candidates associated with beiging included POMC and CGRP. • POMC cleavage product α-MSH caused beiging of cultured fat cells.

Objective Activation of thermogenesis in brown adipose tissue (BAT) and the ability to increase uncoupling protein 1 (UCP1) levels and mitochondrial biogenesis in white fat (termed ‘browning’), has great therapeutic potential to treat obesity and its comorbidities because of the net increase in energy expenditure. β-adrenergic-cAMP-PKA signaling has long been known to regulate these processes. Recently PKA-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) was shown to be necessary for adipose ‘browning’ as well as proper development of the interscapular BAT. In addition to cAMP-PKA signaling pathways, cGMP-PKG signaling also promotes this browning process; however, it is unclear whether or not mTORC1 is also necessary for cGMP-PKG induced browning. Method Activation of mTORC1 by natriuretic peptides (NP), which bind to and activate the membrane-bound guanylyl cyclase, NP receptor A (NPRA), was assessed in mouse and human adipocytes in vitro and mouse adipose tissue in vivo. Results Activation of mTORC1 by NP-cGMP signaling was observed in both mouse and human adipocytes. We show that NP-NPRA-PKG signaling activate mTORC1 by direct PKG phosphorylation of Raptor at Serine 791. Administration of B-type natriuretic peptide (BNP) to mice induced Ucp1 expression in inguinal adipose tissue in vivo, which was completely blocked by the mTORC1 inhibitor rapamycin. Conclusion Our results demonstrate that NP-cGMP signaling activates mTORC1 via PKG, which is a component in the mechanism of adipose browning., Graphical abstract, Highlights • Natriuretic peptide-cGMP signaling activates mTORC1 in adipocytes in vitro. • Natriuretic peptide-cGMP signaling activates mTORC1 in adipose tissue in vivo. • Natriuretic peptides signaling stimulates Raptor phosphorylation. • mTORC1 is necessary for BNP-evoked browning of inguinal white adipose tissue in vivo.

Therapeutic potential of metformin in obese/diabetic patients has been associated to its ability to combat insulin resistance. However, it remains largely unknown the signaling pathways involved and whether some cell types are particularly relevant for its beneficial effects. M1-activation of macrophages by bacterial lipopolysaccharide (LPS) promotes a paracrine activation of hypoxia-inducible factor-1α (HIF1α) in brown adipocytes which reduces insulin signaling and glucose uptake, as well as β-adrenergic sensitivity. Addition of metformin to M1-polarized macrophages blunted these signs of brown adipocyte dysfunction. At the molecular level, metformin inhibits an inflammatory program executed by HIF1α in macrophages by inducing its degradation through the inhibition of mitochondrial complex I activity, thereby reducing oxygen consumption in a reactive oxygen species (ROS)-independent manner. In obese mice, metformin reduced inflammatory features in brown adipose tissue (BAT) such as macrophage infiltration, proinflammatory signaling and gene expression, and restored the response to cold exposure. In conclusion, the impact of metformin on macrophages by suppressing a HIF1α-dependent proinflammatory program is likely responsible for a secondary beneficial effect on insulin-mediated glucose uptake and β-adrenergic responses in brown adipocytes., Graphical abstract Image 1, Highlights • Macrophage-mediated inflammation in brown adipocytes stabilizes HIF1α. • Stabilization of HIF1α reduces brown adipocyte hormonal responses. • Metformin attenuates inflammation and BAT dysfunction in obese mice. • Mitochondrial complex I inhibition by metformin reduces HIF1α in macrophages. • Targeting macrophages HIF1α by metformin alleviates brown adipocyte inflammation.

Obesity is a global health problem that is often related to cardiovascular and metabolic diseases. Chronic low-grade inflammation in white adipose tissue (WAT) is a hallmark of obesity. Previously, during a search for differentially expressed genes in WAT of obese mice, we identified glycoprotein nonmetastatic melanoma protein B (GPNMB), of which expression was robustly induced in pathologically expanded WAT. Here, we investigated the role of GPNMB in obesity-related metabolic disorders utilizing GPNMB-deficient mice. When fed a high-fat diet (HFD), GPNMB-deficient mice showed body weight and adiposity similar to those of wild-type (WT) mice. Nonetheless, insulin and glucose tolerance tests revealed significant obesity-related metabolic disorders in GPNMB-KO mice compared with WT mice fed with HFD. Chronic WAT inflammation was remarkably worsened in HFD-fed GPNMB-KO mice, accompanied by a striking increase in crown-like structures, typical hallmarks for diseased WAT. Macrophages isolated from GPNMB-KO mice were observed to produce more inflammatory cytokines than those of WT mice, a difference abolished by supplementation with recombinant soluble GPNMB extracellular domain. We demonstrated that GPNMB reduced the inflammatory capacity of macrophages by inhibiting NF-κB signaling largely through binding to CD44. Finally, we showed that macrophage depletion by addition of clodronate liposomes abolished the worsened WAT inflammation and abrogated the exacerbation of metabolic disorders in GPNMB-deficient mice fed on HFD. Our data reveal that GPNMB negatively regulates macrophage inflammatory capacities and ameliorates the WAT inflammation in obesity; therefore we conclude that GPNMB is a promising therapeutic target for the treatment of metabolic disorders associated with obesity.

Objective Brown and white adipose tissue exerts pleiotropic effects on systemic energy metabolism in part by releasing endocrine factors. Neuregulin 4 (Nrg4) was recently identified as a brown fat-enriched secreted factor that ameliorates diet-induced metabolic disorders, including insulin resistance and hepatic steatosis. However, the physiological mechanisms through which Nrg4 regulates energy balance and glucose and lipid metabolism remain incompletely understood. The aims of the current study were: i) to investigate the regulation of adipose Nrg4 expression during obesity and the physiological signals involved, ii) to elucidate the mechanisms underlying Nrg4 regulation of energy balance and glucose and lipid metabolism, and iii) to explore whether Nrg4 regulates adipose tissue secretome gene expression and adipokine secretion. Methods We examined the correlation of adipose Nrg4 expression with obesity in a cohort of diet-induced obese mice and investigated the upstream signals that regulate Nrg4 expression. We performed metabolic cage and hyperinsulinemic-euglycemic clamp studies in Nrg4 transgenic mice to dissect the metabolic pathways regulated by Nrg4. We investigated how Nrg4 regulates hepatic lipid metabolism in the fasting state and explored the effects of Nrg4 on adipose tissue gene expression, particularly those encoding secreted factors. Results Adipose Nrg4 expression is inversely correlated with adiposity and regulated by pro-inflammatory and anti-inflammatory signaling. Transgenic expression of Nrg4 increases energy expenditure and augments whole body glucose metabolism. Nrg4 protects mice from diet-induced hepatic steatosis in part through activation of hepatic fatty acid oxidation and ketogenesis. Finally, Nrg4 promotes a healthy adipokine profile during obesity. Conclusions Nrg4 exerts pleiotropic beneficial effects on energy balance and glucose and lipid metabolism to ameliorate obesity-associated metabolic disorders. Biologic therapeutics based on Nrg4 may improve both type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) in patients., Highlights • Nrg4 is a target of pro-inflammatory and anti-inflammatory signaling in adipocytes. • Transgenic expression of Nrg4 increased energy expenditure and glucose metabolism. • Nrg4 stimulates hepatic fatty acid oxidation and ketogenesis during starvation. • Nrg4 promotes a beneficial adipokine profile during obesity.

Metabolic diseases such as type 2 diabetes are a major public health issue worldwide. These diseases are often linked to a dysfunctional adipose tissue. Fat is a large, heterogenic, pleiotropic and rather complex tissue. It is found in virtually all cavities of the human body, shows unique plasticity among tissues, and harbors many cell types in addition to its main functional unit – the adipocyte. Adipose tissue function varies depending on the localization of the fat depot, the cell composition of the tissue and the energy status of the organism. While the white adipose tissue (WAT) serves as the main site for triglyceride storage and acts as an important endocrine organ, the brown adipose tissue (BAT) is responsible for thermogenesis. Beige adipocytes can also appear in WAT depots to sustain heat production upon certain conditions, and it is becoming clear that adipose tissue depots can switch phenotypes depending on cell autonomous and non-autonomous stimuli. To maintain such degree of plasticity and respond adequately to changes in the energy balance, three basic processes need to be properly functioning in the adipose tissue: i) adipogenesis and adipocyte turnover, ii) metabolism, and iii) signaling. Here we review the fundamental role of small non-coding RNAs (sncRNAs) in these processes, with focus on microRNAs, and demonstrate their importance in adipose tissue function and whole body metabolic control in mammals., Graphical abstract fx1, Highlights • Adipose tissue dysfunction is a major cause of metabolic diseases. • Adipose tissue function is determined by three hallmarks: adipogenesis, metabolism and signaling. • Small non-coding RNAs (particularly microRNAs) are causally linked to these hallmarks in adipose tissue. • Changes in microRNA expression in adipose tissue occur in physiological conditions and in disease. • Adipose tissue microRNAs control whole body metabolism and organismal homeostasis.

Objective Alternative activation (M2) of adipose tissue resident macrophage (ATM) inhibits obesity-induced metabolic inflammation. The underlying mechanisms remain unclear. Recent studies have shown that dysregulated lipid homeostasis caused by increased lipolysis in white adipose tissue (WAT) in the obese state is a trigger of inflammatory responses. We investigated the role of M2 macrophages in lipotoxicity-induced inflammation. Methods We used microarray experiments to profile macrophage gene expression regulated by two M2 inducers, interleukin-4 (Il-4), and peroxisome proliferator-activated receptor delta/gamma (Pparδ/Pparγ) agonists. Functional validation studies were performed in bone marrow-derived macrophages and mice deprived of the signal transducer and activator of transcription 6 gene (Stat6; downstream effector of Il-4) or Pparδ/Pparγ genes (downstream effectors of Stat6). Palmitic acid (PA) and β-adrenergic agonist were employed to induce macrophage lipid loading in vitro and in vivo, respectively. Results Profiling of genes regulated by Il-4 or Pparδ/Pparγ agonists reveals that alternative activation promotes the cell survival program, while inhibiting that of inflammation-related cell death. Deletion of Stat6 or Pparδ/Pparγ increases the susceptibility of macrophages to PA-induced cell death. NLR family pyrin domain containing 3 (Nlrp3) inflammasome activation by PA in the presence of lipopolysaccharide is also increased in Stat6−/− macrophages and to a lesser extent, in Pparδ/γ−/− macrophages. In concert, β-adrenergic agonist-induced lipolysis results in higher levels of cell death and inflammatory markers in ATMs derived from myeloid-specific Pparδ/γ−/− or Stat6−/− mice. Conclusions Our data suggest that ATM cell death is closely linked to metabolic inflammation. Within WAT where concentrations of free fatty acids fluctuate, M2 polarization regulated by the Stat6-Ppar axis enhances ATM's tolerance to lipid-mediated stress, thereby maintaining the homeostatic state., Highlights • Cell survival is transcriptionally regulated by macrophage alternative activation. • Fatty acid-triggered cell death is increased in Pparδ/γ−/− or Stat6−/− macrophages. • Il-4-Stat6 signaling suppresses lipotoxicity-induced inflammasome activation. • The Stat6-Pparδ/γ axis protects ATMs against lipolysis-induced cell death in vivo.

Objective A potential strategy to treat obesity – and the associated metabolic consequences – is to increase energy expenditure. This could be achieved by stimulating thermogenesis through activation of brown adipose tissue (BAT) and/or the induction of browning of white adipose tissue (WAT). Over the last years, it has become clear that several metalloproteinases play an important role in adipocyte biology. Here, we investigated the potential role of ADAMTS5. Methods Mice deficient in ADAMTS5 (Adamts5−/−) and wild-type (Adamts5+/+) littermates were kept on a standard of Western-type diet for 15 weeks. Energy expenditure and heat production was followed by indirect calorimetry. To activate thermogenesis, mice were treated with the β3-adrenergic receptor (β3-AR) agonist CL-316,243 or alternatively, exposed to cold for 2 weeks. Results Compared to Adamts5+/+ mice, Adamts5−/− mice have significantly more interscapular BAT and marked browning of their subcutaneous (SC) WAT. Thermogenic pathway analysis indicated, in the absence of ADAMTS5, enhanced β3-AR signaling via activation of the cAMP response element-binding protein (CREB). Additional β3-AR stimulation with CL-316,243 promoted browning of WAT in Adamts5+/+ mice but had no additive effect in Adamts5−/− mice. However, cold exposure induced more pronounced browning of WAT in Adamts5−/− mice. Conclusions These data indicate that ADAMTS5 plays a functional role in development of BAT and browning of WAT. Hence, selective targeting of ADAMTS5 could provide a novel therapeutic strategy for treatment/prevention of obesity and metabolic diseases., Highlights • Mice deficient in ADAMTS5 have elevated interscapular brown adipose tissue mass. • ADAMTS5 deficient mice show increased browning of their white adipose tissue. • The thermogenic profile is enhanced via adrenergic signaling and CREB activation. • ADAMTS5 seems an attractive therapeutic target for metabolic diseases.

金沢大学医薬保健研究域医学系, Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion (UGE), leading to blood glucose reductions and weight loss. However, the impacts of SGLT2 inhibition on energy homeostasis and obesity-induced insulin resistance are less well known. Here, we show that empagliflozin, a SGLT2 inhibitor, enhanced energy expenditure and attenuated inflammation and insulin resistance in high-fat-diet-induced obese (DIO) mice. C57BL/6J mice were pair-fed a high-fat diet (HFD) or a HFD with empagliflozin for 16 weeks. Empagliflozin administration increased UGE in the DIO mice, whereas it suppressed HFD-induced weight gain, insulin resistance, and hepatic steatosis. Moreover, empagliflozin shifted energy metabolism towards fat utilization, elevated AMP-activated protein kinase and acetyl-CoA carbolxylase phosphorylation in skeletal muscle, and increased hepatic and plasma fibroblast growth factor 21 levels. Importantly, empagliflozin increased energy expenditure, heat production, and the expression of uncoupling protein 1 in brown fat and in inguinal and epididymal white adipose tissue (WAT). Furthermore, empagliflozin reduced M1-polarized macrophage accumulation while inducing the anti-inflammatory M2 phenotype of macrophages within WAT and liver, lowering plasma TNFα levels and attenuating obesity-related chronic inflammation. Thus, empagliflozin suppressed weight gain by enhancing fat utilization and browning and attenuated obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in WAT and liver.

Obesity and its related metabolic disorders are closely correlated with gut dysbiosis. Montmorillonite is a common medicine used to treat diarrhea. We have previously found that dietary lipid adsorbent-montmorillonite (DLA-M) has an unexpected role in preventing obesity. The aim of this study was to further investigate whether DLA-M regulates intestinal absorption and gut microbiota to prevent obesity-related metabolic disorders. Here, we show that DLA-M absorbs free fatty acids (FFA) and endotoxins in vitro and in vivo. Moreover, the combination of fluorescent tracer technique and polarized light microscopy showed that DLA-M crystals immobilized BODIPY® FL C16 and FITC-LPS, respectively, in the digestive tract in situ. HFD-fed mice treated with DLA-M showed mild changes in the composition of the gut microbiota, particularly increases in short-chain fatty acids (SCFA)-producing Blautia bacteria and decreases in endotoxin-producing Desulfovibrio bacteria, these changes were positively correlated with obesity and inflammation. Our results indicated that DLA-M immobilizes FFA and endotoxins in the digestive tract via the adsorption-excretion axis and DLA-M may potentially be used as a prebiotic to prevent intestinal dysbiosis and obesity-associated metabolic disorders in obese individuals., Highlights • Montmorillonite prevents obesity-associated metabolic disorders in obese individuals. • Montmorillonite immobilizes triglycerides, cholesterol, FFA and endotoxin in the digestive tract via the adsorption-excretion axis. • Montmorillonite may potentially be used as a prebiotic to modulate the gut microbiota composition in HFD-fed mice. Obesity and its related insulin resistance, hepatic steatosis are closely correlated with low-grade inflammation and gut dysbiosis. Montmorillonite is initially characterized as a commonly gastrointestinal mucosal barrier protective agent for the treatment of diarrhea. The purpose of this work is to assess the ability of montmorillonite on preventing obesity-related metabolic disorders and the underlying mechanisms. The results of our experiments provide some theoretical reference for the instruction purpose of clinical medication on montmorillonite.