The Skinny on Adiponectin

Abstract

The search for mechanisms connecting regulation of body weight and eating has been a long one, beginning with the early hypothalamic lesion studies by Hetherington and Ranson (1) and others indicating the importance of certain nuclei in the regulation of appetite and body weight (see Ref. 2). Subsequent experiments in which the circulations of hypothalamic-lesioned and control animalswereconnected indicated the importanceof circulating factors in the changes in body weight (2, 3) Experiments focusing on the chemical messengers that affected food intake began in the early 1960s (4) and have continued to this day (e.g. ref. 5). Of the many chemical messengers regulating energy balance, one standout has been leptin, a cytokine that acts at both peripheral and central targets to suppress food intake and promote a state of negative energy balance (6). Leptin, which is produced by white adipose tissue in proportion to the fat mass (7), has been seen to act in the brain in a coordinated fashion to activate proopiomelanocortin neurons of the hypothalamic arcuate nucleus that release the anorexigenic signal, -MSH and, concomitantly, inhibit neurons that release the orexigenic signals Neuropeptide Y and Agouti-related peptide (5, 8). This link has proven a durable model of the interactions between the periphery and the brain but also relies on the relatively unusual role of a leptin transporter to bring the signal past the blood-brain barrier, in contrast to the more conventionally understood visceral afferent pathways (9, 10) or the more recently described responses of sensory circumventricular organs to circulating energy balance-related signals (11). Since the discovery of leptin, it has become clear that adipose tissue is an endocrine organ (12), secreting an increasing number of recognized signals (13). One of these is adiponectin, whose circulating concentration is not only very high, but is also inversely proportional to adiposity (14). Disruption of adiponectin signaling results in obesity (15). Receptors for adiponectin are expressed in a variety of neuronal populations, including the area postrema (a sensory circumventricular organ), the arcuate nucleus, and the paraventricular nucleus (PVN). Earlier work has shown that both the area postrema (11) and PVN (16, 17) are sensitive to energy balance-related signals, including adiponectin (18, 19). In the present report, Hoyda et al. (20) begin by noting that the PVN contains neurons that regulate both autonomic and neuroendocrine function, and that injection of adiponectin into the brain causes weight loss and affects autonomic functions such as thermogenesis, and elevates mRNA levels of the stressrelated hormone CRH in parvocellular neurons of the PVN. The parvocellular neurons of the PVN can be divided into two categories by firing pattern: the steadily firing neuroendocrine (NE) cells, with axons projecting to the median eminence and the burst-firing preautonomic (PA) neurons, with axons projecting to the spinal cord (21–23). These neurons make a variety of different peptides, including CRH, TRH, and oxytocin (OT), which can act as neuromodulators or hormones, depending on whether they are released into the median eminence or the spinal cord. Neuroendocrine projections to the median eminence regulate release of hormones such as ACTH and thyroid-stimulating hormone, whereas the preautonomic projections to the nucleus of the solitary tract mediate thermoregulatory information or signals related to energy balance (24, 25). The effects of adiponectin were determined on parvocellular PVN neurons that were identified as NE or PA based on their electrophysiological properties and by their neuropeptide expression, determined by single-cell RT-PCR. Application of adiponectin to both NE and PA neurons influenced their membrane potential and, in some cases, their firing rate. Most neurons tested depolarized in response to adiponectin, whereas a smaller proportion hyperpolarized, and some did not respond. Adiponectin acted directly on these cells because blockade of synaptic transmission with tetrodotoxin did not affect the actions of adiponectin. The authors observed that NE cells that expressed mRNA for CRH were depolarized by adiponectin, consistent with earlier evidence. These neurons also expressed mRNA for at least one of the two known adiponectin receptors; importantly, neurons that did not express receptor mRNA were largely unaffected by adiponectin. Consistent with these results, injection of adiponectin into the lateral ventricle in vivo resulted in dose-dependent elevation in plasma ACTH concentrations, a consequence of neuroendocrine CRH release. Adiponectin also depolarized PA neurons that made TRH