Cover Story Current Issue
Despite intensive drug development efforts and public health initiatives, obesity is increasing in incidence and predicted to affect over 50% of all adults worldwide by 2035. Being chronically overweight increases the risk of serious disease co-morbidities that, in turn, increase mortality and healthcare costs. Behavioral approaches to combat obesity, such as diet and exercise, rarely produce lasting weight loss commonly due to compensatory hyperphagia and hypometabolism. These limitations have stimulated interest in pharmacotherapies that target gut-derived peptide hormones involved in the regulation of energy homeostasis, such as PYY, GIP, CCK, and GLP-1. These peptides are secreted by different enteroendocrine cells distributed throughout the intestine in response to food intake, subsequently enhancing satiation signaling and ultimately promotes meal termination. However, a major challenge of FDA-approved and experimental weight-loss medications that target GI-derived satiation signals is the frequent occurrence of nausea and vomiting.
Current Issue
TRPC6 governs brown adipose thermogenesis via a BMPR2-p38 MAPK signaling axis
TRPC6 governs brown adipose thermogenesis via a BMPR2-p38 MAPK signaling axis
Brown adipose tissue (BAT) thermogenesis combats obesity, but mechanisms linking calcium dynamics to thermogenic programming remain incompletely defined. Here, we identify the calcium channel TRPC6 as an essential BAT-intrinsic regulator of metabolic health. BAT-specific Trpc6 knockout (Trpc6BTKO) mice exhibit spontaneous BAT whitening, mitochondrial dysfunction, and impaired cold tolerance. Upon high-fat diet (HFD) challenge, Trpc6BTKO mice develop exacerbated obesity, hepatic steatosis, and insulin resistance. These phenotypes are driven by increased energy intake and reduced energy expenditure associated with impaired thermogenesis. TRPC6 deficiency suppresses mitochondrial biogenesis and thermogenesis. Mechanistically, TRPC6 mediates calcium influx and interacts directly with BMPR2, thereby selectively activating p38 MAPK signaling to drive thermogenic gene expression. Genetic disruption of the TRPC6-BMPR2 complex abolishes TRPC6-mediated thermogenesis. Thus, we define a non-redundant TRPC6-BMPR2-p38 MAPK signaling axis whose disruption underpins obesity and associated metabolic dysfunction, positioning it as a promising therapeutic target for metabolic disease.
Articles in Press
TRPC6 governs brown adipose thermogenesis via a BMPR2-p38 MAPK signaling axis
TRPC6 governs brown adipose thermogenesis via a BMPR2-p38 MAPK signaling axis
Brown adipose tissue (BAT) thermogenesis combats obesity, but mechanisms linking calcium dynamics to thermogenic programming remain incompletely defined. Here, we identify the calcium channel TRPC6 as an essential BAT-intrinsic regulator of metabolic health. BAT-specific Trpc6 knockout (Trpc6BTKO) mice exhibit spontaneous BAT whitening, mitochondrial dysfunction, and impaired cold tolerance. Upon high-fat diet (HFD) challenge, Trpc6BTKO mice develop exacerbated obesity, hepatic steatosis, and insulin resistance. These phenotypes are driven by increased energy intake and reduced energy expenditure associated with impaired thermogenesis. TRPC6 deficiency suppresses mitochondrial biogenesis and thermogenesis. Mechanistically, TRPC6 mediates calcium influx and interacts directly with BMPR2, thereby selectively activating p38 MAPK signaling to drive thermogenic gene expression. Genetic disruption of the TRPC6-BMPR2 complex abolishes TRPC6-mediated thermogenesis. Thus, we define a non-redundant TRPC6-BMPR2-p38 MAPK signaling axis whose disruption underpins obesity and associated metabolic dysfunction, positioning it as a promising therapeutic target for metabolic disease.
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Helmholtz Diabetes Conference
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You are what you eat
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