Role of Hypothalamic VGF in Energy Balance and Metabolic Adaption to Environmental Enrichment in Mice

Abstract

Environmental enrichment (EE), a housing condition providing complex physical, social, and cognitive stimulation, leads to improved metabolic health and resistance to diet-induced obesity and cancer. One underlying mechanism is the activation of the hypothalamic-sympathoneuraladipocyte axis with hypothalamic brain-derived neurotrophic factor (BDNF) as the key mediator. VGF, a peptide precursor particularly abundant in the hypothalamus, was up-regulated by EE. Overexpressing BDNF or acute injection of BDNF protein to the hypothalamus up-regulated VGF, whereas suppressing BDNF signaling down-regulated VGF expression. Moreover, hypothalamic VGF expression was regulated by leptin, melanocortin receptor agonist, and food deprivation mostly paralleled to BDNF expression. Recombinant adeno-associated virus-mediated gene transfer of Cre recombinase to floxed VGF mice specifically decreased VGF expression in the hypothalamus. In contrast to the lean and hypermetabolic phenotype of homozygous germline VGF knockout mice, specific knockdown of hypothalamic VGF in male adult mice led to increased adiposity, decreased core body temperature, reduced energy expenditure, and impaired glucose tolerance, as well as disturbance of molecular features of brown and white adipose tissues without effects on food intake. However, VGF knockdown failed to block the EE-induced BDNF upregulation or decrease of adiposity indicating a minor role of VGF in the hypothalamicsympathoneural-adipocyte axis. Taken together, our results suggest hypothalamic VGF responds to environmental demands and plays an important role in energy balance and glycemic control likely acting in the melanocortin pathway downstream of BDNF. (Endocrinology 2016(Endocrinology : 34-46, 2016 I n 2014, 52% of adults worldwide were overweight or obese, thus this epidemic has undoubtedly become a global health, social, and economic problem (1, 2). Substantial obesity-related morbidity and mortality have prompted many investigations to explore genes involved in metabolic regulation. We previously manipulated the environment and demonstrated that environ-mental enrichment (EE), a housing condition providing complex stimuli, leads to robust improvements in metabolism including decreased adiposity, resistance to diet-induced obesity, and mitigation of obesity-associated liver steatosis and insulin resistance in addition to inhibition of peripheral cancers (3-5). Moreover, our mechanistic studies have elucidated a novel neuroendocrine axis, the hypothalamic-sympathoneural-adipocyte (HSA) axis, underlying the EE-induced resistance to obesity and