Leptin Sensitive Neurons in the Hypothalamus

Abstract

A major paradigm in the field of obesity research is the existence of an adipose tissue-brain endocrine axis for the regulation of body weight. Leptin, the peptide mediator of this axis, is secreted by adipose cells. It lowers food intake and body weight by acting in the hypothalamus, a region expressing an abundance of leptin receptors and a variety of neuropeptides that influence food intake and energy balance. Among the most promising candidates for leptin-sensitive cells in the hypothalamus are arcuate nucleus neurons that co-express the anabolic neuropeptides, neuropeptide Y (NPY) and agouti-related peptide (AGRP), and those that express proopiomelanocortin (POMC), the precursor of the catabolic peptide, alphaMSH. These cell types contain mRNA encoding leptin receptors and show changes in neuropeptide gene expression in response to changes in food intake and circulating leptin levels. Decreased leptin signaling in the arcuate nucleus is hypothesized to increase the expression of NPY and AGRP. Levels of leptin receptor mRNA and leptin binding are increased in the arcuate nucleus during fasting, principally in NPY/AGRP neurons. These findings suggest that changes in leptin receptor expression in the arcuate nucleus are inversely associated with changes in leptin signaling, and that the arcuate nucleus is an important target of leptin action in the brain.

Lean rats with hypothalamic pro-opiomelanocortin overexpression exhibit greater diet-induced obesity and impaired central melanocortin responsiveness

“…Considerable evidence indicates that the melanocortin system is downstream of the hypothalamic leptin-signalling pathway. Leptin activates POMC neurons and suppresses agouti-related protein (AGRP) in the arcuate nucleus (ARC), resulting in a rise in Pomc expression and a reduction in Agrp mRNA [14][15][16][17][18]. Moreover, the upregulation of Pomc by leptin is impaired in leptin resistance associated with diet-induced obesity and adult-onset obesity [19,20].…”

Unabated anorexic and enhanced thermogenic responses to melanotan II in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression

“…A growing body of evidence suggests that the MC system is located downstream of the hypothalamic leptin-signaling pathway. Leptin activates POMC-and suppresses AgRPcontaining neurons of the ventrolateral and ventromedial arcuate nucleus respectively, resulting in an increase in the expression of POMC and a reduction in AgRP (Schwartz et al 1996, Cheung et al 1997, Baskin et al 1999, Elias et al 2000. It is possible that the central resistance is partially due to a failure of the leptin signal to activate POMC or suppress AgRP neurons so that the proper regulation of POMC and AgRP expression by leptin is lost.…”

Adrenalectomy Alters the Sensitivity of the Central Nervous System Melanocortin System

“…Genetic leptin deficiency results in profound hyperphagia and obesity in mice and humans (9), a syndrome that can be reversed by exogenous leptin treatment (10 -12). These effects of leptin are due to activation of the leptin receptor in brain regions important for body weight regulation (5), including the hypothalamic arcuate nucleus (ARC) and adjacent areas (13).…”

“…MCs (including ␣-melanocyte-stimulating hormone [␣-MSH]) are cleavage products of proopiomelanocortin (POMC), which is synthesized by neurons in the ARC. These neurons express the long form of the leptin receptor (13), are activated by leptin, and project to other nuclei within the hypothalamus, including the paraventricular nucleus (PVN) (19), where MC3 and MC4 receptors are located (20 -22). Central administration of ␣-MSH (23,24), or its synthetic analog, melanotan II (MTII), dose dependently reduces food intake in rodents (25,26), and endogenous melanocortin signaling is required for normal body weight regulation (18,27,28) The effects of ␣-MSH are opposed by agouti-related protein (AgRP), an endogenous antagonist of MC3 and MC4 receptors (29) synthesized in ARC neurons that also synthesize neuropeptide Y. Glucocorticoids are implicated as negative regulators of melanocortin signaling because ADX reduces AgRP expression in the hypothalamus of normal mice and normalizes hypothalamic levels of POMC mRNA and AgRP mRNA in ob/ob mice (30).…”