Identifying the fundamental molecular factors that drive
weight gain even in the absence of hypercaloric food intake, is crucial to enable development of novel treatments for the global pandemic of
obesity. Here we investigated both adipose tissue-specific and systemic events that underlie the physiological
weight gain occurring during early adulthood in mice fed a normocaloric diet. In addition, we used three different genetic models to identify molecular factors that promote physiological
weight gain during normocaloric and hypercaloric diets. We demonstrated that normal physiological
weight gain was accompanied by an increase in adipose tissue mass and the presence of cellular and metabolic signatures typically found during
obesity, including adipocyte
hypertrophy, macrophage recruitment into visceral fat and perturbed
glucose metabolism. At the molecular level, this was associated with an increase in adipose tissue
tryptophan hydroxylase 1 (Tph1) transcripts, the key
enzyme responsible for the synthesis of peripheral
serotonin. Genetic inactivation of Tph1 was sufficient to limit adipose tissue expansion and associated metabolic alterations. Mechanistically, we discovered that Tph1 inactivation resulted in down-regulation of
cyclin-dependent kinase inhibitor p21Waf1/Cip1 expression. Single or double ablation of Tph1 and p21 were equally effective in preventing adipocyte expansion and systemic perturbation of
glucose metabolism, upon both normocaloric and hypercaloric diets. Our results suggest that
serotonin and p21 act as a central molecular determinant of
weight gain and associated metabolic alterations, and highlights the potential of targeting these molecules as a pharmacologic approach to prevent the development of
obesity.