Brain nuclear receptors and body weight regulation

Introduction Obesity is a serious global health problem due to its increasing prevalence and comorbidities. Over 30% of Americans are obese (1). Obese individuals are at an increased risk for developing type 2 diabetes, cardiovascular disease, and cancer. These observations highlight the urgent need to better understand the physiology of body weight control, which may facilitate the development of more effective therapies for obesity. The brain, including the hypothalamus, integrates information regarding the body’s nutritional status and orchestrates a series of coordinated endocrine, autonomic, and behavioral responses that regulate body weight (2–4). Development of Cre-loxP conditional gene manipulation and more recent circuit functional mapping using optogenetic and chemogenetic approaches have facilitated advances in our understanding of how complex brain neural circuits regulate energy homeostasis, particularly within the hypothalamus. Among the numerous hypothalamic nuclei, the arcuate nucleus of the hypothalamus (ARH) has received the most extensive attention. In particular, ARH neurons that express proopiomelanocortin (POMC) and those that co-release neuropeptide Y, agouti-related peptide (AgRP), and GABA (referred to as AgRP neurons in this Review) have long been believed to be the primary central regulators of energy homeostasis (5, 6). POMC neurons synthesize and secrete an anorexigenic peptide, α-melanocyte-stimulating hormone (α-MSH), which prevents overeating and body weight gain (7, 8), while AgRP neurons are indispensable for normal feeding and survival (9, 10), as activation of AgRP neurons rapidly promotes eating even when mice are satiated (11, 12). Inhibitory AgRP neurons project locally to POMC neurons and to a number of distant targets throughout the brain; the latter include the paraventricular nucleus of the hypothalamus (PVH), the paraventricular nucleus of the thalamus (PVT), the parabrachial nucleus (PBN), the bed nucleus of stria terminalis (BNST), the lateral hypothalamic area (LHA), and the medial amygdala (MeA). Many of these projections (e.g., POMC, PVH, PVT, PBN, BNST, and LHA) have been shown to promote feeding behavior (9, 13–15). In addition, subsets of neurons in the PVH project to and activate AgRP neurons to trigger feeding (16). While α-MSH activates melanocortin-4 receptors (MC4Rs) to prevent body weight gain, AgRP (as an endogenous antagonist) inhibits MC4Rs to promote body weight gain. In particular, MC4Rs expressed in the PVH and MeA specifically inhibit food intake (17). In particular, PVH MC4R neurons suppress food intake by projecting to the PBN (18), while the targets mediating anorexigenic effects of MeA MC4R neurons remain unknown. ARH AgRP neurons also provide inhibitory GABAergic inputs to PBN neurons to promote feeding (9, 19). The PBN receives excitatory inputs from glutamatergic neurons in the nucleus tractus solitarius (NTS), and activation of these PBN neurons inhibits feeding (15). The LHA is another complex hypothalamic nucleus that plays an essential role in feeding control. Activation of glutamatergic neurons in the LHA inhibits feeding (20) through their projections to the lateral habenula (21); in contrast, activation of GABAergic neurons in the LHA promotes feeding (22, 23) through their projections to the PVH (22). While we do not intend to systemically review the complex brain neural circuits that regulate energy homeostasis (please see refs. 24–26 for excellent reviews on this topic), it is clear that numerous brain structures, including the ARH, PVH, LHA, MeA, PBN, NTS, and many more, are heavily involved in the regulation of body weight balance (Figure 1). Nuclear receptors (NRs) represent a large family of transcription factors found in all metazoan species (27). Many NRs have known endogenous ligands, including endocrine steroids (i.e., corticosteroids, progesterone, androgens, and estrogens), fat-soluble vitamins A and D, thyroid hormone, fatty acids, oxysterols, bile acids, and numerous diet-derived xenobiotic lipids (28). Additional members of the NR family are called orphan receptors because their ligands remain unknown. NRs govern the expression of genes involved in a broad range of biological processes, including reproduction, development, immune responses, Neural pathways, especially those in the hypothalamus, integrate multiple nutritional, hormonal, and neural signals, resulting in the coordinated control of body weight balance and glucose homeostasis. Nuclear receptors (NRs) sense changing levels of nutrients and hormones, and therefore play essential roles in the regulation of energy homeostasis. Understanding the role and the underlying mechanisms of NRs in the context of energy balance control may facilitate the identification of novel targets to treat obesity. Notably, NRs are abundantly expressed in the brain, and emerging evidence indicates that a number of these brain NRs regulate multiple aspects of energy balance, including feeding, energy expenditure and physical activity. In this Review we summarize some of the recent literature regarding effects of brain NRs on body weight regulation and discuss mechanisms underlying these effects. Brain nuclear receptors and body weight regulation