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Background Obesity is a complex disease marked by excessive, dysfunctional adipose tissue accumulation. Recent research underscores the pivotal role of brown adipose tissue (BAT) in metabolic health and its potential as a therapeutic target for obesity management. Emerging preclinical and clinical evidence suggests that second-generation anti-obesity drugs, especially dual agonists such as tirzepatide, may enhance BAT activity. Additionally, beige adipose tissue, derived from white adipose tissue (WAT), may contribute significantly to whole-body thermogenesis, yet its role remains underexplored. Methods This investigator-initiated, randomized, placebo-controlled clinical trial aims to evaluate the effects of tirzepatide on BAT activity and WAT browning in premenopausal women with obesity. Thirty-four participants will be randomized 1:1 to receive either tirzepatide or a placebo for 24 weeks. Primary outcomes include changes in BAT volume and activity, assessed using 18F-FDG-PET/CT, MRI, and infrared thermography, as well as the induction of WAT browning, evaluated through changes in mRNA expression patterns and histomorphometric alterations in subcutaneous adipose tissue samples. Secondary outcomes will involve the assessment of whole-body composition, resting energy expenditure, and various metabolic health markers, correlated with thermogenic adipose tissue changes. Comparative analysis of BAT assessment methods will refine protocols for research and clinical use. Discussion This study is the first to systematically explore the potential of pharmacological obesity management to enhance BAT activity and induce WAT browning. Results may establish thermogenic adipose tissue augmentation as a novel mechanism of action for second-generation anti-obesity medications. Trial registration ClinicalTrials.gov NCT06893211. Registered on 2025 March 25.

Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue—brown especially—into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3′ UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine. Adipose tissue is a major source of circulating exosomal miRNAs, which contribute to the regulation of gene expression in distant tissues and organs. A novel form of adipokine Adipose tissue is best known as a site of energy storage, but it also has a role in the regulation of metabolism through the release of cell signalling molecules called adipokines. Here Ronald Kahn and colleagues show that adipose tissue constitutes a major source of circulating exosomal microRNAs (miRNAs), and that these miRNAs are able to regulate gene expression in distant tissues. The miRNAs can therefore be considered to be a form of adipokine.

Our understanding of adipose tissue biology has progressed rapidly since the turn of the century. White adipose tissue has emerged as a key determinant of healthy metabolism and metabolic dysfunction. This realization is paralleled only by the confirmation that adult humans have heat-dissipating brown adipose tissue, an important contributor to energy balance and a possible therapeutic target for the treatment of metabolic disease. We propose that the development of successful strategies to target brown and white adipose tissues will depend on investigations that elucidate their developmental origins and cell-type-specific functional regulators.

Mammalian adipose tissue is traditionally categorized into white and brown relating to their function and morphology: while white serves as an energy storage, brown adipose tissue acts as the heat generator maintaining the core body temperature. The most recently identified type of fat, beige adipocyte tissue, resembles brown fat by morphology and function but is developmentally more related to white. The synthesis of beige fat, so-called browning of white fat, has developed into a topical issue in diabetes and metabolism research. This is due to its favorable effect on whole-body energy metabolism and the fact that it can be recruited during adult life. Indeed, brown and beige adipose tissues have been demonstrated to play a role in glucose homeostasis, insulin sensitivity, and lipid metabolism—all factors related to pathogenesis of type 2 diabetes. Many agents capable of initiating browning have been identified so far and tested widely in humans and animal models including in vitro and in vivo experiments. Interestingly, several agents demonstrated to have browning activity are in fact secreted as adipokines from brown and beige fat tissue, suggesting a physiological relevance both in beige adipocyte recruitment processes and in maintenance of metabolic homeostasis. The newest findings on agents driving beige fat recruitment, their mechanisms, and implications on type 2 diabetes are discussed in this review.

Thermogenesis by brown and beige adipose tissue, which requires activation by external stimuli, can counter metabolic disease 1 . Thermogenic respiration is initiated by adipocyte lipolysis through cyclic AMP–protein kinase A signalling; this pathway has been subject to longstanding clinical investigation 2 – 4 . Here we apply a comparative metabolomics approach and identify an independent metabolic pathway that controls acute activation of adipose tissue thermogenesis in vivo. We show that substantial and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. Succinate accumulation occurs independently of adrenergic signalling, and is sufficient to elevate thermogenic respiration in brown adipocytes. Selective accumulation of succinate may be driven by a capacity of brown adipocytes to sequester elevated circulating succinate. Furthermore, brown adipose tissue thermogenesis can be initiated by systemic administration of succinate in mice. Succinate from the extracellular milieu is rapidly metabolized by brown adipocytes, and its oxidation by succinate dehydrogenase is required for activation of thermogenesis. We identify a mechanism whereby succinate dehydrogenase-mediated oxidation of succinate initiates production of reactive oxygen species, and drives thermogenic respiration, whereas inhibition of succinate dehydrogenase supresses thermogenesis. Finally, we show that pharmacological elevation of circulating succinate drives UCP1-dependent thermogenesis by brown adipose tissue in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance. These findings reveal an unexpected mechanism for control of thermogenesis, using succinate as a systemically-derived thermogenic molecule. A comparative metabolomics approach is used to identify succinate as a key activator of thermogenesis in brown adipose tissue.

Expression of bone morphogenetic protein 4 (BMP4) in adipocytes of white adipose tissue (WAT) produces “white adipocytes” with characteristics of brown fat and leads to a reduction of adiposity and its metabolic complications. Although BMP4 is known to induce commitment of pluripotent stem cells to the adipocyte lineage by producing cells that possess the characteristics of preadipocytes, its effects on the mature white adipocyte phenotype and function were unknown. Forced expression of a BMP4 transgene in white adipocytes of mice gives rise to reduced WAT mass and white adipocyte size along with an increased number of a white adipocyte cell types with brown adipocyte characteristics comparable to those of beige or brite adipocytes. These changes correlate closely with increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. Conversely, BMP4-deficient mice exhibit enlarged white adipocyte morphology and impaired insulin sensitivity. We identify peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as the target of BMP signaling required for these brown fat-like changes in WAT. This effect of BMP4 on WAT appears to extend to human adipose tissue, because the level of expression of BMP4 in WAT correlates inversely with body mass index. These findings provide a genetic and metabolic basis for BMP4’s role in altering insulin sensitivity by affecting WAT development.

Significance High levels of brown/beige fat activity protects animals against metabolic disease, but there has been little known about the precursor cells that mediate the expansion of brown or beige fat. We discovered that early B-cell factor 2 (Ebf2), a transcription factor, is selectively expressed in brown and beige fat cell precursors. Through purification of Ebf2 ⁺ cells, we identified a gene profile of brown fat precursors that can be used to distinguish these cells from other developmentally related cell types. Importantly, Ebf2 was also found to regulate the gene expression profile of brown fat precursor cells. Taken together, this study identifies Ebf2 as a highly specific marker of brown and beige preadipose cells and reveals that Ebf2 functions to control brown preadipose cell identity. Brown adipocytes and muscle and dorsal dermis descend from precursor cells in the dermomyotome, but the factors that regulate commitment to the brown adipose lineage are unknown. Here, we prospectively isolated and determined the molecular profile of embryonic brown preadipose cells. Brown adipogenic precursor activity in embryos was confined to platelet-derived growth factor α ⁺, myogenic factor 5 Cʳᵉ-lineage–marked cells. RNA-sequence analysis identified early B-cell factor 2 ( Ebf2 ) as one of the most selectively expressed genes in this cell fraction. Importantly, Ebf2 -expressing cells purified from Ebf2 ᴳFᴾ embryos or brown fat tissue did not express myoblast or dermal cell markers and uniformly differentiated into brown adipocytes. Interestingly, Ebf2 -expressing cells from white fat tissue in adult animals differentiated into brown-like (or beige) adipocytes. Loss of Ebf2 in brown preadipose cells reduced the expression levels of brown preadipose-signature genes, whereas ectopic Ebf2 expression in myoblasts activated brown preadipose-specific genes. Altogether, these results indicate that Ebf2 specifically marks and regulates the molecular profile of brown preadipose cells.

When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.

Qiong Wang and colleagues introduce the AdipoChaser mouse, an in vivo tool to track the formation and turnover of adipocytes. They use this inducible mature adipocyte lineage-tracing system to monitor adipogenesis and follow the formation of white and beige adipocytes under different conditions: high-fat diet, cold exposure and β-adrenergic stimulation. The system produced some interesting findings on in vivo adipogenesis, including that beige adipocytes differentiate de novo from specialized precursors rather than by transdifferentiation of mature white adipocytes. White adipose tissue displays high plasticity. We developed a system for the inducible, permanent labeling of mature adipocytes that we called the AdipoChaser mouse. We monitored adipogenesis during development, high-fat diet (HFD) feeding and cold exposure. During cold-induced 'browning' of subcutaneous fat, most 'beige' adipocytes stem from de novo –differentiated adipocytes. During HFD feeding, epididymal fat initiates adipogenesis after 4 weeks, whereas subcutaneous fat undergoes hypertrophy for a period of up to 12 weeks. Gonadal fat develops postnatally, whereas subcutaneous fat develops between embryonic days 14 and 18. Our results highlight the extensive differences in adipogenic potential in various fat depots.

Aims/hypothesisThe aim of this study was to evaluate the effect of sitagliptin on glucose tolerance, plasma lipids, energy expenditure and metabolism of brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscle in overweight individuals with prediabetes (impaired glucose tolerance and/or impaired fasting glucose).MethodsWe performed a randomised, double-blinded, placebo-controlled trial in 30 overweight, Europid men (age 45.9 ± 6.2 years; BMI 28.8 ± 2.3 kg/m2) with prediabetes in the Leiden University Medical Center and the Alrijne Hospital between March 2015 and September 2016. Participants were initially randomly allocated to receive sitagliptin (100 mg/day) (n = 15) or placebo (n = 15) for 12 weeks, using a randomisation list that was set up by an unblinded pharmacist. All people involved in the study as well as participants were blinded to group assignment. Two participants withdrew from the study prior to completion (both in the sitagliptin group) and were subsequently replaced with two new participants that were allocated to the same treatment. Before and after treatment, fasting venous blood samples and skeletal muscle biopsies were obtained, OGTT was performed and body composition, resting energy expenditure and [18F] fluorodeoxyglucose ([18F]FDG) uptake by metabolic tissues were assessed. The primary study endpoint was the effect of sitagliptin on BAT volume and activity.ResultsOne participant from the sitagliptin group was excluded from analysis, due to a distribution error, leaving 29 participants for further analysis. Sitagliptin, but not placebo, lowered glucose excursion (−40%; p < 0.003) during OGTT, accompanied by an improved insulinogenic index (+38%; p < 0.003) and oral disposition index (+44%; p < 0.003). In addition, sitagliptin lowered serum concentrations of triacylglycerol (−29%) and very large (−46%), large (−35%) and medium-sized (−24%) VLDL particles (all p < 0.05). Body weight, body composition and energy expenditure did not change. In skeletal muscle, sitagliptin increased mRNA expression of PGC1β (also known as PPARGC1B) (+117%; p < 0.05), a main controller of mitochondrial oxidative energy metabolism. Although the primary endpoint of change in BAT volume and activity was not met, sitagliptin increased [18F] FDG uptake in subcutaneous WAT (sWAT; +53%; p < 0.05). Reported side effects were mild and transient and not necessarily related to the treatment.Conclusions/interpretationTwelve weeks of sitagliptin in overweight, Europid men with prediabetes improves glucose tolerance and lipid metabolism, as related to increased [18F] FDG uptake by sWAT, rather than BAT, and upregulation of the mitochondrial gene PGC1β in skeletal muscle. Studies on the effect of sitagliptin on preventing or delaying the progression of prediabetes into type 2 diabetes are warranted.Trial registrationClinicalTrials.gov NCT02294084.FundingThis study was funded by Merck Sharp & Dohme Corp, Dutch Heart Foundation, Dutch Diabetes Research Foundation, Ministry of Economic Affairs and the University of Granada.