Abstract
Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) combusts energy to produce heat. Here we show that a small molecule stimulator (BAY 41-8543) of soluble guanylyl cyclase (sGC), which produces the second messenger cyclic GMP (cGMP), protects against diet-induced weight gain, induces weight loss in established obesity, and also improves the diabetic phenotype. Mechanistically, the haeme-dependent sGC stimulator BAY 41–8543 enhances lipid uptake into BAT and increases whole-body energy expenditure, whereas ablation of the haeme-containing β1-subunit of sGC severely impairs BAT function. Notably, the sGC stimulator enhances differentiation of human brown adipocytes as well as induces ‘browning' of primary white adipocytes. Taken together, our data suggest that sGC is a potential pharmacological target for the treatment of obesity and its comorbidities.
Highlights
Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT)
The results of our study show that pharmacological soluble guanylyl cyclase (sGC) stimulation protects against diet-induced obesity (DIO) and induces weight loss in already established obesity
The changes in body weight induced by the sGC stimulator are accompanied by improved overall metabolic status as indicated by improved glucose tolerance, decreased liver steatosis, reduced insulin levels and decreased adipocyte size in WATi, a parameter for healthy expansion of WAT36
Summary
Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). Brown adipose tissue (BAT) combusts energy to produce heat. When energy intake constantly exceeds energy expenditure (EE), the surplus is stored as lipids in white adipose tissue (WAT) leading to the development of obesity. WAT serves as the major energy storage and has endocrine functions It secretes adipokines such as leptin or tumour-necrosis factor-a, which can affect metabolism and can enhance inflammation[3]. In contrast to WAT, brown adipose tissue (BAT) dissipates energy and generates heat by nonshivering thermogenesis. Cold exposure results in the release of norepinephrine (NE) from sympathetic nerves in BAT and subsequent activation of b-adrenergic receptors that couple via Gs protein to adenylate cylcase, thereby stimulating cAMP production. It has been shown recently that adenosine is a sympathetic co-transmitter that induces cAMP production via A2A receptors in BAT19. cAMP-initiated lipolysis results in the release of free fatty acids and activation of UCP1, which disrupts the mitochondrial proton gradient and causes the production of heat instead of ATP4
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