Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance because such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, we show that a designer protein-deprived diet enriched in free essential amino acids can 1) promote the brown fat thermogenic program and fatty acid oxidation, 2) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, 3) change the gut microbiota composition, and 4) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy life span. These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by in vitro experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.

Cyclic nucleotides cAMP and cGMP are important second messengers for the regulation of adaptive thermogenesis. Their levels are controlled not only by their synthesis, but also their degradation. Since pharmacological inhibitors of cGMP-specific phosphodiesterase 9 (PDE9) can increase cGMP-dependent protein kinase signaling and uncoupling protein 1 expression in adipocytes, we sought to elucidate the role of PDE9 on energy balance and glucose homeostasis in vivo. Mice with targeted disruption of the PDE9 gene, Pde9a, were fed nutrient-matched high-fat (HFD) or low-fat diets. Pde9a -/- mice were resistant to HFD-induced obesity, exhibiting a global increase in energy expenditure, while brown adipose tissue (AT) had increased respiratory capacity and elevated expression of Ucp1 and other thermogenic genes. Reduced adiposity of HFD-fed Pde9a -/- mice was associated with improvements in glucose handling and hepatic steatosis. Cold exposure or treatment with β-adrenergic receptor agonists markedly decreased Pde9a expression in brown AT and cultured brown adipocytes, while Pde9a -/- mice exhibited a greater increase in AT browning, together suggesting that the PDE9-cGMP pathway augments classical cold-induced β-adrenergic/cAMP AT browning and energy expenditure. These findings suggest PDE9 is a previously unrecognized regulator of energy metabolism and that its inhibition may be a valuable avenue to explore for combating metabolic disease.