The growing complexity of the control of the hypothalamic pituitary thyroid axis and brown adipose tissue by leptin

The balance between food intake and energy expenditure is precisely regulated to maintain adipose stores. Leptin, which is produced in and released from adipose in direct proportion to its size, is a major contributor to this control and initiates its homeostatic responses largely via binding to leptin receptors (LepR) in the hypothalamus. Decreases in hypothalamic LepR binding signals starvation, leading to hunger and reduced energy expenditure, whereas increases in hypothalamic LepR binding can suppress food intake and increase energy expenditure. However, large gaps persist in the specific hypothalamic sites and detailed mechanisms by which leptin increases energy expenditure, via the parallel activation of the hypothalamic pituitary thyroid (HPT) axis and brown adipose tissue (BAT). The purpose of this review is to develop a framework for the complex mechanisms and neurocircuitry. The core circuitry begins with leptin binding to receptors in the arcuate nucleus, which then sends projections to the paraventricular nucleus (to regulate the HPT axis) and the dorsomedial hypothalamus (to regulate BAT). We build on this core by layering complexities, including the intricate and unsettled regulation of arcuate proopiomelanocortin neurons by leptin and the changes that occur as the regulation of the HPT axis and BAT is engaged or modified by challenges such as starvation, hypothermia, obesity, and pregnancy.