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Natural remedies are used as standalone treatments or complementary to modern medicine to control type 2 diabetes. In Palau, the traditional leaf decoction of Phaleria nisidai (PNe) is selected to treat hyperglycemia and its efficacy has been supported by a small clinical trial. As part of a reverse pharmacology approach, we here investigated the anti-diabetic potential of PNe and its bioactive compounds to alleviate insulin resistance in diet-induced obese, male mice. Dietary supplementation with PNe improves insulin sensitivity and promotes glucose uptake into adipose depots. In vitro, PNe triggers glucose disposal into murine and human adipocytes by upregulating Glut1 expression through PKC-ERK1/2 signaling. To identify active constituents in PNe, we conducted bioactivity-guided fractionations and deciphered genkwanin flavone glycosides as bioactive principles. Moreover, we demonstrate that the aglycone genkwanin (GE) improves insulin resistance to a comparable extent to the anti-diabetic drug, metformin. Our findings present GE as promising glucoregulatory phytochemical that facilitates glucose uptake into adipocytes, thereby reducing systemic glucose load and enhancing insulin sensitivity. Here the authors show that genkwanin glycosides from Phaleria nisida i leaf extract improve glucose homeostasis by enhancing glucose uptake into adipose tissue, with effects comparable to metformin in a study with male mice with obesity and insulin resistance.

Aims/hypothesisIn the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy.MethodsWe studied the role of antioxidants in the regulation of insulin resistance using the tamoxifen-inducible fat-specific insulin receptor knockout (iFIRKO) mouse model, which allowed us to analyse the antioxidant’s effect in a time-resolved manner. In addition, leptin-deficient ob/ob mice were used as a hyperphagic, chronically obese and diabetic mouse model to validate the beneficial effect of antioxidants on metabolism.ResultsAcute induction of insulin receptor knockout in adipocytes changed the substrate preference to fat before induction of a diabetic phenotype including hyperinsulinaemia and hyperglycaemia. In healthy chow-fed animals as well as in morbidly obese mice, this diabetic phase could be reversed within a few weeks. Furthermore, after the induction of insulin receptor knockout in mature adipocytes, iFIRKO mice were protected from subsequent obesity development through high-fat diet feeding. By genetic tracing we show that the persistent fat mass loss in mice after insulin receptor knockout in adipocytes is not caused by the depletion of adipocytes. Treatment of iFIRKO mice with antioxidants postponed and reduced hyperglycaemia by increasing insulin sensitivity. In ob/ob mice, antioxidants rescued both hyperglycaemia and hyperphagia.Conclusions/interpretationWe conclude that fat mass reduction through insulin resistance in adipocytes is not reversible. Furthermore, it seems unlikely that adipocytes undergo apoptosis during the process of extreme lipolysis, as a consequence of insulin resistance. Antioxidants have a beneficial health effect not only during the acute phase of diabetes development, but also in a temporary fashion once chronic obesity and diabetes have been established.

Activation of thermogenic brown and beige adipocytes is considered as a strategy to improve metabolic control. Here, we identify GPR180 as a receptor regulating brown and beige adipocyte function and whole-body glucose homeostasis, whose expression in humans is associated with improved metabolic control. We demonstrate that GPR180 is not a GPCR but a component of the TGFβ signalling pathway and regulates the activity of the TGFβ receptor complex through SMAD3 phosphorylation. In addition, using genetic and pharmacological tools, we provide evidence that GPR180 is required to manifest Collagen triple helix repeat containing 1 (CTHRC1) action to regulate brown and beige adipocyte activity and glucose homeostasis. In this work, we show that CTHRC1/GPR180 signalling integrates into the TGFβ signalling as an alternative axis to fine-tune and achieve low-grade activation of the pathway to prevent pathophysiological response while contributing to control of glucose and energy metabolism. Activation of thermogenic adipocytes is a strategy to combat metabolic diseases. Here the authors report that GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1, and contributes to the regulation of glucose and energy metabolism.

The current obesity epidemic and high prevalence of metabolic diseases necessitate efficacious and safe treatments. Brown adipose tissue in this context is a promising target with the potential to increase energy expenditure, however no pharmacological treatments activating brown adipose tissue are currently available. Here, we identify AXL receptor tyrosine kinase as a regulator of adipose function. Pharmacological and genetic inhibition of AXL enhance thermogenic capacity of brown and white adipocytes, in vitro and in vivo. Mechanistically, these effects are mediated through inhibition of PI3K/AKT/PDE signaling pathway, resulting in induction of nuclear FOXO1 localization and increased intracellular cAMP levels via PDE3/4 inhibition and subsequent stimulation of the PKA-ATF2 pathway. In line with this, both constitutive Axl deletion as well as inducible adipocyte-specific Axl deletion protect animals from diet-induced obesity concomitant with increases in energy expenditure. Based on these data, we propose AXL receptor as a target for the treatment of obesity. Brown adipose tissue is a promising target for the treatment of obesity with the potential to increase energy expenditure. Here, the authors use pharmacological and genetic approaches to block AXL receptor activation and show that its inhibition enhances brown adipocyte functionality and thermogenesis, leading to weight loss and metabolic improvements in mice.

Excessive adipose accumulation, which is the main driver for the development of secondary metabolic complications, has reached epidemic proportions and combined pharmaceutical, educational and nutritional approaches are required to reverse the current rise in global obesity prevalence rates. Brown adipose tissue (BAT) is a unique organ able to dissipate energy and thus a promising target to enhance BMR to counteract a positive energy balance. In addition, active BAT might support body weight maintenance after weight loss to prevent/reduce relapse. Natural products deliver valuable bioactive compounds that have historically helped to alleviate disease symptoms. Interest in recent years has focused on identifying nutritional constituents that are able to induce BAT activity and thereby enhance energy expenditure. This review provides a summary of selected dietary phytochemicals, including isoflavones, catechins, stilbenes, the flavonoids quercetin, luteolin and resveratrol as well as the alkaloids berberine and capsaicin. Most of the discussed phytochemicals act through distinct molecular pathways e.g. sympathetic nerve activation, AMP-kinase signalling, SIRT1 activity or stimulation of oestrogen receptors. Thus, it might be possible to utilise this multitude of pathways to co-activate BAT using a fine-tuned combination of foods or combined nutritional supplements.

PRDM16 is a key mediator of thermogenic fat, counteracting adipose fibrosis and inflammation. Kajimura and co-authors demonstrate that a CUL2–APPBP2 ubiquitin E3 ligase complex destabilizes the PRDM16 protein, resulting in declined metabolic activity in an age-dependent manner.

Despite the high utility and widespread use of Cre driver lines, lack of Cre specificity, Cre-induced toxicity or poor experimental design can affect experimental results and conclusions. Such pitfalls must be considered before embarking on any Cre-based studies in metabolic research.

Adipocyte function is a major determinant of metabolic disease, warranting investigations of regulating mechanisms. We show at single-cell resolution that progenitor cells from four human brown and white adipose depots separate into two main cell fates, an adipogenic and a structural branch, developing from a common progenitor. The adipogenic gene signature contains mitochondrial activity genes, and associates with genome-wide association study traits for fat distribution. Based on an extracellular matrix and developmental gene signature, we name the structural branch of cells structural Wnt-regulated adipose tissue-resident (SWAT) cells. When stripped from adipogenic cells, SWAT cells display a multipotent phenotype by reverting towards progenitor state or differentiating into new adipogenic cells, dependent on media. Label transfer algorithms recapitulate the cell types in human adipose tissue datasets. In conclusion, we provide a differentiation map of human adipocytes and define the multipotent SWAT cell, providing a new perspective on adipose tissue regulation. Single-cell transcriptomic analysis of progenitor cells from human adipose depots reveals an adipogenic and a structural branch of cells, the latter named SWAT cells and shown to display a multipotent phenotype.

The dual glucagon/glucagon-like peptide 1 receptor (GCGR/GLP1R) agonists have superior efficacy in promoting weight loss and metabolic improvements in obesity and metabolic dysfunction-associated steatohepatitis (MASH) than current available mono-agonists. However, the mechanisms underlying these benefits are not fully understood. While the effects on appetite regulation and glucose control through GLP1R agonism are well established, the role of GCGR agonism in promoting weight loss and metabolic changes is less defined. Using a dual GCGR/GLP1R agonist BI 456908 and a selective GLP1R agonist semaglutide, we could show that the dual agonist achieved superior weight loss efficacy by engaging hepatic GCGR without adversely affecting glucose control. Furthermore, we could demonstrate that hepatic GCGR is critical for facilitating plasma and liver lipid clearance stimulated by the dual agonist. Overall, these findings highlight the crucial metabolic contributions of hepatic GCGR to the efficacy of combined GCGR/GL1R activation.

Regulation of lipid metabolism is fundamental for metabolic health, and adipose tissue is a central component in this process. Adipose tissue differs dramatically between women and men with a higher subcutaneous capacity for storage and healthy metabolism in women. Sex hormone-binding globulin (SHBG) contributes to the regulation of circulating sex hormone bioavailability and has been shown to predict risk of metabolic dysfunction. We here investigate the sex-specific relationship of SHBG with metabolic status and adipocyte-dependent lipolysis. We measured serum concentrations of sex hormones, SHBG, fasting glucose and insulin in a cohort of 63 women and 27 men from which adipose biopsies were collected and mature adipocytes were isolated. We found that, in women, high serum SHBG concentrations were strongly associated with low HOMA-IR in vivo, and lower baseline lipolysis but higher responsiveness to isopropanol-induced lipolysis ex vivo. In contrast, no effect of SHBG on the above-mentioned parameters were observed in men. In vitro, cultured adipocytes also increased lipolytic capacity in response to SHBG, but only in the absence of testosterone, suggesting that testosterone inhibits the catecholmine-induced lipolysis of SHBG in adipose tissue. In conclusion, we here define a novel role for SHBG in adipocyte lipolysis. At the same time, our data emphasize sex-dependent differences in adipocyte lipid metabolism, and we propose testosterone binding to SHBG as a driving factor mediating these differences.Competing Interest StatementThe authors have declared no competing interest.