The Hypothalamus: Central Appetite Regulation

Feeding and energy expenditure are controlled by complex neural networks distributed throughout the forebrain and brainstem. Homeostatic feeding behavior is integrated within the hypothalamus. 

Key peripheral signals of energy status such as gut hormones and adipokines either signal to the hypothalamus directly or indirectly via the brainstem and vagal afferent fibres. Adiposity signals such as insulin and leptin are involved in the long-term energy homeostasis, and gut hormones such as ghrelin are implicated in the short-term regulation of meal ingestion [1-3]. The Hypothalamus comprises various nuclei, of which the arcuate nucleus (ARC), the paraventricular nucleus (PVN), the ventromedial nucleus (VMN), the dorsomedial nucleus (DMN), and the lateral hypothalamic area (LHA) play a role in energy homeostasis.

Hypothalamic Orexigenic and Anorexigenic Neuropeptides
The ARC, known as the infundibular nucleus in man, is situated at the base of the hypothalamus. It contacts the peripheral circulation through semi-permeable capillaries in the underlying median eminence and is thus in an ideal position to integrate hormonal signals for energy homeostasis. In the ARC, there are two important discrete neuronal populations: Neurons coexpressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) stimulate food intake, whereas neurons coexpressing pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) suppress food intake. Both subpopulations project to the LHA and PVN, where they control the function of second-order neurons. In the PVN, two distinct subpopulations of neurons produce the anorexigenic (appetite-suppressing) neurotransmitters thyrotropin-releasing hormone, and corticotropin-releasing hormone. In contrast to this, in the LHA, two other subpopulations produce the orexigenic (appetite-stimulating) neurotransmitter orexin (hypocretin) and melanin-concentrating hormone (for review see [4, 5]).

Peripheral Hormones and Peptides Regulating Appetite
Leptin, predominantly synthesized in adipose tissue, inhibits NPY/AgRP neurons and stimulates POMC/CART neurons. Circulating leptin levels are directly proportional to adiposity in animals and humans. Insulin, which is produced in the β cells of the pancreas and rapidly secreted after a meal, binds to insulin receptors on the surface of POMC/CART neurons and activates them. The rise in circulating insulin in response to a glucose load is proportional to fat mass. Ghrelin, a hormone from the stomach, exerts a stimulating effect when binding at growth hormone secretagogue receptors on NPY/AgRP neurons. Circulating ghrelin decreases in response to chronic overfeeding and increases in response to chronic negative energy balance associated with exercise or anorexia nervosa. Whereas obese people usually have high plasma leptin, they have low plasma ghrelin (for review see [6]).

[1] Simpson et al., Arc Bras Endocrinol Metabol, 2009
[2] Stanley et al., Physiol Rev, 2005
[3] Suzuki et al., Endocr J, 2010
[4] Velloso et al., Neuroimmunomodulation, 2008
[5] Suzuki et al., Exp Diabetes Res, 2012
[6] Neary et al., Clin Endocrinol (Oxf.), 2004

By Charlotte Klein, PhD Alumna AG Neural Regeneration and Plasticity  
This article originally appeared 2012 in CNS Volume 5, Issue 4, Fat Gut or Fat Brain