ABSTRACT
Body weight and fat stores are determined by the net excess or deficit of food intake over energy expenditure. The hypothalamus acts centrally to integrate redundant signaling pathways involving the neuroendocrine and autonomic nervous systems to determine food intake, energy expenditure, and nutrient partitioning. Leptin and insulin are secreted in proportion to peripheral fat mass, and signal the hypothalamus regarding the state of long-term energy stores (Fig. 1) (1). Leptin appears to act primarily to signal critical minimal energy (triglyceride) reserves for functions such as reproduction (2). Low concentrations of leptin and insulin generate an anabolic signal to increase food intake and reduce energy expenditure (3). Leptin and insulin bind to receptors on neurons in the arcuate nucleus, which is partially outside of the blood brain barrier. As detailed in Chapters 3.1 and 3.2. The arcuate nucleus contains two discrete neuronal populations producing either Agouti-related protein (AgRP) and Neuropeptide Y (NPY), or proopiomelanocortin (POMC) and cocaine and amphetamine regulated transcript (CART) that act reciprocally to increase and decrease food intake, respectively, and to transduce outflow signals regulating body fat stores (1). Leptin and insulin inhibit the NPY/AgRP neurons and reciprocally stimulate the POMC/CART neurons. Agouti-related protein is the naturally occurring inverse agonist of MC3R and MC4R (melanocortin 3 and 4 receptors) and is expressed in cell bodies in the arcuate that coexpress NPY and that project to “second order” nuclei expressing MC3R and MC4R to stimulate food intake. The “default” action of this neural system is to generate a net anabolic signal unless leptin and insulin signal sufficient energy stores. Both sets of neurons respond vigorously to starvation, but only the POMC/CART neurons respond to excess energy intake in part explaining why it is easier for individuals to gain rather than lose weight. Energy expenditure is then coordinated through the autonomic nervous system and hypothalamic control of thyroid function.
