The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.

In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, this increase in LAM abundance is strongly p53 dependent and partly mediated by p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation during IF, increases the catabolic state of adipocytes, and enhances systemic metabolic flexibility and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to efficacy of a fasting-mimicking diet and that the expression of p53 and TREM2 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signalling in adipocytes dictates LAM accumulation in AT under IF and modulates fasting effectiveness in mice and humans.

The dramatically increasing world-wide prevalence of obesity is recognized as a risk factor for the development of various diseases. The growing research on the role of adipose tissue in controlling energy homeostasis and insulin sensitivity has revealed that the promotion of brown adipose tissue (BAT) activity and the browning of white adipose tissue (WAT) leads to multiple health benefits and prevents obesity and type 2 diabetes (T2D). Inducible thermogenic adipocytes do exist in adult humans and are linked with increased energy combustion and lower body fat mass. Thus brown adipocytes are currently placed at the center of attention for novel therapeutic strategies against metabolic diseases such as obesity and diabetes. Besides the classical, norepinephrine-mediated sympathetic recruitment and activation of thermogenic adipocytes, a number of novel circulating factors have been recently identified to have a positive or negative impact on thermogenic adipocyte formation and activity. In this review their mechanism of action and the plausible therapeutic applications will be summarized and discussed.

Brown adipose tissue (BAT) dissipates energy via non-shivering thermogenesis, but durable thermogenic benefit requires sustained cold remodeling that stabilizes a cold-adapted tissue state. While most studies have focused on adipocyte-intrinsic pathways that drive acute activation, how stromal niche cells-particularly the vasculature-sense and coordinate long-term adaptation remains poorly defined. Because GPCRs are key sensors of extracellular and neurohumoral cues, we mapped GPCR expression across mouse and human BAT at single-nucleus resolution and identified adhesion GPCRs as a prominent family enriched in vascular cells, with endothelial ADGRF5(GPR116) emerging as a leading candidate regulator. Single-nucleus RNA sequencing of mouse and human BAT was used to map GPCR expression across cell types. Global, inducible endothelial-specific, and adipocyte-specific ADGRF5(GPR116) knockout mouse models were each challenged with acute and prolonged cold exposure. Endothelial and adipocyte states were analyzed using single-nucleus RNA sequencing transcriptional profiling, functional vascular assays, and cell-cell communication modeling. Endothelial deletion of ADGRF5(GPR116) impaired the ability of mice to sustain thermogenesis during prolonged cold exposure, whereas adipocyte-specific deletion did not affect thermogenic capacity in vivo. Loss of endothelial ADGRF5(GPR116) did not alter endothelial cell abundance, but induced endothelial transcriptional reprogramming characterized by disrupted quiescent remodeling programs, shifts in endothelial state with EndMT-like features, and context-dependent alterations in barrier-associated pathways, occurring in the absence of immune cell infiltration or overt fibrosis. Adipocyte reclustering revealed a failure to acquire a fully cold-adapted thermogenic state, with thermogenically inefficient programs and adrenergic hyporesponsiveness, despite preserved sympathetic input. CellChat and NicheNet analyses predicted altered endothelial-derived paracrine signaling capable of reshaping adipocyte identity. Endothelial ADGRF5(GPR116) is a critical regulator of vascular adaptation during sustained cold exposure and supports full acquisition of the thermogenic adipocyte state through endothelial identity and paracrine signaling.

Cancer cachexia is a devastating wasting syndrome with no approved therapies. In this study, we identify the tumor-derived glycoprotein ADAMTSL4 as a circulating factor associated with body weight loss in preclinical cachexia models and patients with colorectal and lung cancers. In mice, Adamtsl4 overexpression converted non–cachexia-inducing tumors into cachexia-inducing tumors, whereas its deletion in cachexia-inducing tumors spared fat and muscle, blunted muscle atrophy signatures, and reduced cachexia severity. ADAMTSL4 engages the latency-associated peptide (LAP) of TGFβ1, promoting local activation of TGFβ1 at muscle cell membranes. Genetic blockade of proTGFβ1 or pharmacologic inhibition of TGFβ signaling reduced ADAMTSL4-dependent wasting in adipocytes and muscle cells. Suppression of tumor-derived ADAMTSL4 attenuated skeletal muscle fibrosis in mice. Together, the association between increased circulating ADAMTSL4 levels and TGFβ–driven muscle atrophy and fibrosis gene signatures in patients with cachectic cancer identifies ADAMTSL4 as an upstream regulator of TGFβ1 and a potential therapeutic target in cancer cachexia. Significance: Cancer cachexia lacks effective therapies and remains a major cause of cancer-related morbidity and mortality. We identify tumor-derived ADAMTSL4 as an upstream regulator of latent TGFβ activation via LAP engagement that promotes multiorgan wasting and fibrosis-related remodeling. Targeting ADAMTSL4 may provide a selective therapeutic strategy without systemic TGFβ pathway blockade. See related commentary by Liu and Janowitz, p. 1964

Brown adipose tissue (BAT) is a key thermogenic organ, whose activation in response to cold environmental temperatures and β‐adrenergic stimulation requires the proper function of the NCOR/HDAC3 corepressor complex in brown adipocytes. The NCOR/HDAC3 complex is large and multi‐component, including the transducin beta‐like 1 (TBL1) and TBL1‐related 1 (TBLR1) proteins. Loss of TBL1 in the hepatocytes and TBLR1 in the white adipocytes has been shown to impair fasting‐ and β‐adrenergic‐induced lipolysis. However, their roles in BAT thermogenesis remain unknown. Here, we report that deletion of TBLR1 alone in brown adipocytes does not impair the adaptive thermogenic response to prolonged cold exposure. In contrast, simultaneous deletion of TBL1 and TBLR1 dampens β‐adrenergic‐induced lipolysis and mitochondrial respiration in cultured mouse brown adipocytes. Transgenic mice with UCP1‐Cre mediated double deletion of TBLR1 and TBL1 exhibit reduced whole‐body energy expenditure during prolonged cold exposure, lower core body temperature, increased appearance of unilocular adipocytes in BAT, and suppressed expression of metabolic and myogenic PRDM16 target genes. Also, we present some evidence that TBLR1 and TBL1 interact with HDAC3 and PRDM16 in brown adipocytes, potentially suggesting a direct involvement in the PRDM16‐controlled transcriptional program. These findings identify the TBLR1/TBL1 complex as a critical regulator of BAT adaptation to prolonged cold and systemic energy homeostasis, shedding light on the context‐dependent functions of corepressor complexes.