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Brown adipose tissue (BAT) and beige fat function in energy expenditure in part due to their role in thermoregulation, making these tissues attractive targets for treating obesity and metabolic disorders. While prolonged cold exposure promotes de novo recruitment of brown adipocytes, the exact sources of cold-induced thermogenic adipocytes are not completely understood. Here, we identify transient receptor potential cation channel subfamily V member 1 (Trpv1) + vascular smooth muscle (VSM) cells as previously unidentified thermogenic adipocyte progenitors. Single-cell RNA sequencing analysis of interscapular brown adipose depots reveals, in addition to the previously known platelet-derived growth factor receptor (Pdgfr)α-expressing mesenchymal progenitors, a population of VSM-derived adipocyte progenitor cells (VSM-APC) expressing the temperature-sensitive cation channel Trpv1. We demonstrate that cold exposure induces the proliferation of Trpv1 + VSM-APCs and enahnces their differentiation to highly thermogenic adipocytes. Together, these findings illustrate the landscape of the thermogenic adipose niche at single-cell resolution and identify a new cellular origin for the development of brown and beige adipocytes. Shamsi et al. identify vascular smooth muscle cells marked by expression of Trpv1 as a part of the cellular lineage of brown and beige fat. Cold stimulates the expansion and differentiation of Trpv1-expressing progenitors to highly thermogenic adipocytes.

Although visceral adipocytes located within the body’s central core are maintained at approximately 37°C, adipocytes within bone marrow, subcutaneous, and dermal depots are found primarily within the peripheral shell and generally exist at cooler temperatures. Responses of brown and beige/brite adipocytes to cold stress are well studied; however, comparatively little is known about mechanisms by which white adipocytes adapt to temperatures below 37°C. Here, we report that adaptation of cultured adipocytes to 31°C, the temperature at which distal marrow adipose tissues and subcutaneous adipose tissues often reside, increases anabolic and catabolic lipid metabolism, and elevates oxygen consumption. Cool adipocytes rely less on glucose and more on pyruvate, glutamine, and, especially, fatty acids as energy sources. Exposure of cultured adipocytes and gluteal white adipose tissue (WAT) to cool temperatures activates a shared program of gene expression. Cool temperatures induce stearoyl-CoA desaturase-1 (SCD1) expression and monounsaturated lipid levels in cultured adipocytes and distal bone marrow adipose tissues (BMATs), and SCD1 activity is required for acquisition of maximal oxygen consumption at 31°C.

Background Anal sphincter defects are a major cause of fecal incontinence causing negative effects on daily life, social interactions, and mental health. Because human adipose-derived stromal/stem cells (hADSCs) are easier and safer to access, secrete high levels of growth factor, and have the potential to differentiate into muscle cells, we investigated the ability of hADSCs to improve anal sphincter incontinence. Methods The present randomized double-blind clinical trial was performed on patients with sphincter defects. They were categorized into a cell group ( n  = 9) and a control group ( n  = 9). Either 6 × 10 6 hADSCs per 3 ml suspended in phosphate buffer saline (treatment) or 3 ml phosphate buffer saline (placebo) was injected. Two months after surgery, the Wexner score, endorectal sonography, and electromyography (EMG) results were recorded. Results Comparing Wexner scores in the cell group and the control group showed no significant difference. In our EMG and endorectal sonography analysis using ImageJ/Fiji 1.46 software, the ratio of the area occupied by the muscle to total area of the lesion showed a 7.91% increase in the cell group compared with the control group. Conclusion The results of the current study show that injection of hADSCs during repair surgery for fecal incontinence may cause replacement of fibrous tissue, which acts as a mechanical support to muscle tissue with contractile function. This is a key point in treatment of fecal incontinence especially in the long term and may be a major step forward. Trial registration Iranian Registry of Clinical Trials IRCT2016022826316N2 . Retrospectively registered 7 May 2016.

The novel insulin-mimetic adipocytokine visfatin has been linked to the metabolic syndrome, but its regulation has not been characterised to date. Since insulin-mimetic actions of visfatin may be part of the feedback regulation of glucose homeostasis, we hypothesised that visfatin concentrations are influenced by glucose or insulin blood levels in humans. In this randomised, double-blind, placebo-controlled crossover study, nine healthy male subjects (age 26+/-6 years) attended three different study days. On each day, systemic glucose concentrations of 5.0, 8.3 and 11.1 mmol/l were attained by stepwise increases in i.v. infusions of glucose, representing fasting and postprandial conditions. Visfatin plasma concentrations were studied during concomitant exogenous hyperinsulinaemia, inhibition of endogenous insulin production by somatostatin infusion, and placebo time control. Additionally, human adipocytes were cultured to study visfatin release and mRNA expression in vitro. Glucose concentrations of 8.3 and 11.1 mmol/l increased circulating visfatin from baseline concentrations of 0.5+/-0.0 ng/ml to 0.9+/-0.1 and 2.1+/-0.3 ng/ml, respectively (p<0.01). Glucose-induced elevation of visfatin was prevented by co-infusion of insulin or somatostatin (p<0.05). Cultured subcutaneous and visceral adipocytes released an equivalent amount of visfatin upon glucose-concentration- and time-dependent stimulation. Visfatin secretion involved the phosphatidylinositol 3-kinase (PI3-kinase) and protein kinase B (AKT) pathways. The mRNA expression pattern of visfatin was consistent with this altered protein release. Circulating visfatin concentrations are increased by hyperglycaemia. This effect is suppressed by exogenous hyperinsulinaemia or somatostatin infusion. Glucose signalling for visfatin release in adipocytes involves the PI3-kinase/AKT pathway.

Key Points Brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function is coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. Histone modification, DNA methylation and chromatin conformational changes have crucial roles in the determination and maintenance of brown and beige adipocyte fate. Currently, more than 50 transcriptional regulators are known to control brown or beige adipocyte differentiation. A large proportion of the regulators, if not all of them, function through master regulators such as peroxisome proliferator-activated receptor-γ (PPARγ) and their partners CCAAT/enhancer-binding protein-ß (C/EBPβ), PR domain zinc-finger protein 16 (PRDM16) and PPARγ co-activator-1α (PGC1α). Various external stimuli, such as chronic cold exposure and synthetic PPARγ ligands, promote beige adipocyte biogenesis in adipocyte precursors. These cues are sensed by cell surface receptors (such as the β-adrenergic receptor) and nuclear receptors (such as PPARγ), leading to dynamic changes in chromatin structures, as well as changes in expression and activity of the key transcriptional regulators. Embryonic, brown adipocytes, together with beige, brown-like adipocytes induced in white fat depots in response to various stimuli, constitute specialized heat-producing fat cells that contribute to organismal energy expenditure. Important insights have now been gained into the transcriptional and epigenetic regulation of biogenesis and thermogenesis of these cells, opening up new possibilities for the treatment of metabolic disorders. White adipocytes store excess energy in the form of triglycerides, whereas brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function relies on the activation of brown and beige adipocyte-specific gene programmes that are coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. A number of transcriptional and epigenetic regulators are also required for promoting beige adipocyte biogenesis in response to various environmental stimuli. A better understanding of the molecular mechanisms governing the generation and function of brown and beige adipocytes is necessary to allow us to control adipose cell fate and stimulate thermogenesis. This may provide a therapeutic approach for the treatment of obesity and obesity-associated diseases, such as type 2 diabetes.

Brown adipose tissue helps to maintain body temperature in hibernators, rodents and neonatal mammals by converting lipids and glucose into heat, thereby increasing energy expenditure. In addition to classical brown adipocytes, adult rodents—like adult humans—harbour brown-like adipocytes in the predominantly white adipose tissue. The formation of these brite (brown-in-white) adipocytes is a physiological response to chronic cold and their cellular origin is under debate. We show here that cold-induced formation of brite adipocytes in mice is reversed within 5 weeks of warm adaptation, but the brite adipocytes formed by cold stimulation are not eliminated. Genetic tracing and transcriptional characterization of isolated adipocytes demonstrates that they are converted into cells with the morphology and gene expression pattern of white adipocytes. Moreover, these white-typical adipocytes can convert into brite adipocytes on additional cold stimulation. Shifting the balance of this interconversion from the white towards the brite phenotype might provide a new means of counteracting obesity by increasing energy expenditure. Brown adipose cells contribute to body temperature maintenance by converting lipids and glucose into heat, and can be found in white adipose tissue. Wolfrum and colleagues find a population of cells in white adipose tissue that can adopt brown or white characteristics in response to cold.

Recent trials show salicylates improve glycemic control in type 2 diabetes, but the mechanism is poorly understood. Expression of the glucocorticoid-generating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissue is increased in vitro by proinflammatory cytokines and upregulated in obesity. 11β-HSD1 inhibition enhances insulin sensitivity. We hypothesized that salicylates downregulate 11β-HSD1 expression, contributing to their metabolic efficacy. We treated diet-induced obese (DIO) 11β-HSD1-deficient mice and C57Bl/6 mice with sodium salicylate for 4 weeks. Glucose tolerance was assessed in vivo. Tissue transcript levels were assessed by quantitative PCR and enzyme activity by incubation with (3)H-steroid. Two weeks' administration of salsalate was also investigated in a randomized double-blind placebo-controlled crossover study in 16 men, with measurement of liver 11β-HSD1 activity in vivo and adipose tissue 11β-HSD1 transcript levels ex vivo. In C57Bl/6 DIO mice, salicylate improved glucose tolerance and downregulated 11β-HSD1 mRNA and activity selectively in visceral adipose. DIO 11β-HSD1-deficient mice were resistant to these metabolic effects of salicylate. In men, salsalate reduced 11β-HSD1 expression in subcutaneous adipose, and in vitro salicylate treatment reduced adipocyte 11β-HSD1 expression and induced adiponectin expression only in the presence of 11β-HSD1 substrate. Reduced intra-adipose glucocorticoid regeneration by 11β-HSD1 is a novel mechanism that contributes to the metabolic efficacy of salicylates.

Brown and beige adipocytes harbor the thermogenic capacity to adapt to environmental thermal or nutritional changes. Histone methylation is an essential epigenetic modification involved in the modulation of nonshivering thermogenesis in adipocytes. Here, we describe a molecular network leading by KMT5c, a H4K20 methyltransferase, that regulates adipocyte thermogenesis and systemic energy expenditure. The expression of Kmt5c is dramatically induced by a β3-adrenergic signaling cascade in both brown and beige fat cells. Depleting Kmt5c in adipocytes in vivo leads to a decreased expression of thermogenic genes in both brown and subcutaneous (s.c.) fat tissues. These mice are prone to high-fat-diet-induced obesity and develop glucose intolerance. Enhanced transformation related protein 53 (Trp53) expression in Kmt5c knockout (KO) mice, that is due to the decreased repressive mark H4K20me3 on its proximal promoter, is responsible for the metabolic phenotypes. Together, these findings reveal the physiological role for KMT5c-mediated H4K20 methylation in the maintenance and activation of the thermogenic program in adipocytes.

Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease. Fat tissue disorders: Dysfunctional fat cell differentiation An abnormal distribution of fatty tissues associated with certain tissue disorders is driven by disrupted fat cell differentiation. Type 2 familial partial lipodystrophy (FPLD2) is a genetic condition that results in fat being lost from the limbs and accumulating in the face and neck. Giovanna Lattanzi at the National Research Council of Italy in Bologna and co-workers found that fat cell (adipocyte) precursors did not clearly differentiate into either of the two main fatty tissue types, brown or white, in FPLD2 patients. White adipocyte precursors exhibited impaired lipid formation and abnormal levels of brown tissue markers. Conversely, brown adipocyte precursors showed high lipid levels and increased autophagy, a natural process involving degradation and recycling of cellular components. The neck is normally where brown fat accumulates, but FPLD2 patients had adipocytes there displaying white fat characteristics.

The transcription factor nuclear factor I-A (NFIA) is a regulator of brown adipocyte differentiation. Here we show that the C-terminal 17 amino acid residues of NFIA (which we call pro#3 domain) are required for the transcriptional activity of NFIA. Full-length NFIA-but not deletion mutant lacking pro#3 domain-rescued impaired expression of PPARγ, the master transcriptional regulator of adipogenesis and impaired adipocyte differentiation in NFIA-knockout cells. Mechanistically, the ability of NFIA to penetrate chromatin and bind to the crucial Pparg enhancer is mediated through pro#3 domain. However, the deletion mutant still binds to Myod1 enhancer to repress expression of MyoD, the master transcriptional regulator of myogenesis as well as proximally transcribed non-coding RNA called DRReRNA, via competition with KLF5 in terms of enhancer binding, leading to suppression of myogenic gene program. Therefore, the negative effect of NFIA on the myogenic gene program is, at least partly, independent of the positive effect on PPARγ expression and its downstream adipogenic gene program. These results uncover multiple ways of action of NFIA to ensure optimal regulation of brown and beige adipocyte differentiation.