C1q/TNF-related protein 13 (CTRP13), a hormone secreted by adipose tissue (adipokines), helps regulate glucose metabolism in peripheral tissues. We previously reported that CTRP13 expression is increased in obese and hyperphagic leptin-deficient mice, suggesting that it may modulate food intake and body weight. CTRP13 is also expressed in the brain, although its role in modulating whole-body energy balance remains unknown. Here, we show that CTRP13 is a novel anorexigenic factor in the mouse brain. Quantitative PCR demonstrated that food restriction downregulates Ctrp13 expression in mouse hypothalamus, while high-fat feeding upregulates expression. Central administration of recombinant CTRP13 suppressed food intake and reduced body weight in mice. Further, CTRP13 and the orexigenic neuropeptide agouti-related protein (AgRP) reciprocally regulate each other's expression in the hypothalamus: central delivery of CTRP13 suppressed Agrp expression, while delivery of AgRP increased Ctrp13 expression. Food restriction alone reduced Ctrp13 and increased orexigenic neuropeptide gene (Npy and Agrp) expression in the hypothalamus; in contrast, when food restriction was coupled to enhanced physical activity in an activity-based anorexia (ABA) mouse model, hypothalamic expression of both Ctrp13 and Agrp were upregulated. Taken together, these results suggest that CTRP13 and AgRP form a hypothalamic feedback loop to modulate food intake and that this neural circuit may be disrupted in an anorexic-like condition.

During development, prenatal and postnatal factors program homeostatic set points to regulate food intake and body weight in the adult. Combinations of genetic and environmental factors contribute to the development of neural circuitry that regulates whole-body energy homeostasis. Brain-derived neurotrophic factor (Bdnf) and its receptor, Tyrosine kinase receptor B (TrkB), are strong candidates for mediating the reshaping of hypothalamic neural circuitry, given their well-characterized role in the central regulation of feeding and body weight. Here, we employ a chemical-genetic approach using the TrkB(F616A/F616A) knock-in mouse model to define the critical developmental period in which TrkB inhibition contributes to increased adult fat mass. Surprisingly, transient TrkB inhibition in embryos, preweaning pups, and adults all resulted in long-lasting increases in body weight and fat content. Moreover, sex-specific differences in the effects of TrkB inhibition on both body weight and hypothalamic gene expression were observed at multiple developmental stages. Our results highlight both the importance of the Bdnf/TrkB pathway in maintaining normal body weight throughout life and the role of sex-specific differences in the organization of hypothalamic neural circuitry that regulates body weight.

CTRP2 is a secreted plasma protein of the C1q family that enhances glycogen deposition and fat oxidation in cultured myotubes. Its in vivo metabolic function, however, has not been established. We show here that acute and chronic metabolic perturbations induced by fasting or high-fat feeding up-regulated the mRNA expression of Ctrp2 in white adipose tissue without affecting its circulating plasma levels. We generated a transgenic mouse model with elevated circulating levels of CTRP2 to determine its metabolic function in vivo. When fed a low-fat diet, wild-type and CTRP2 transgenic mice exhibited no metabolic phenotypes. When challenged with a high-fat diet to induce obesity, wild-type and CTRP2 transgenic mice had similar weight gain, adiposity, food intake, metabolic rate, and energy expenditure. Fasting serum lipid and adipokine profiles were also similar between the two groups of mice. However, while glucose and insulin levels in the fasted state were comparable between wild-type and CTRP2 transgenic mice, insulin levels in the fed state were consistently lower in transgenic mice. Notably, CTRP2 transgenic mice had improved insulin tolerance and a greater capacity to handle acute lipid challenge relative to littermate controls. Our results highlight, for the first time, the in vivo role of CTRP2 in modulating whole-body metabolism.