MCAT Biological and Biochemical Foundations of Living Systems: Passage 11 — Flashcards

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Energy homeostasis is tightly controlled by the central nervous system (CNS), and in particular a region of the brain called the hypothalamus, in conjunction with peripheral signals that convey information to the CNS. When the process becomes imbalanced, it can lead to metabolic disorders such as obesity, as well as cardiovascular diseases, hypertension, stroke, and type 2 diabetes. The neuronal circuit in the hypothalamus that is most critical for energy homeostasis is called the melanocortin system. This system is made up of three neuronal populations: neurons that express agouti-related peptide (AgRP) and the neuropeptide Y (NPY) and neurons that express proopiomelanocortin, both of which are located in the hypothalamic arcuate nucleus, and neurons that express the melanocortin 4 receptor (MC4R), located in the hypothalamic paraventricular nucleus. POMC neurons are anorexigenic because, by activating MC4R, they reduce food intake and increase energy expenditure. On the other hand, AgRP/NPY neurons are orexigenic because they antagonize the activity of POMC. POMC is a large polypeptide hormone that is processed by proteases that cleave in between basic residues to produce nine proteins. Of these proteins, α-MSH is a well-known anorexigenic molecule that exerts its effect by binding and activating melanocortin receptors. A number of peripheral hormones also regulate the melanocortin neurons, including leptin, insulin, ghrelin, glucocorticoids, and thyroid hormones. In particular, the leptin hormone, which is produced by adipocytes, has received a lot of attention for its potential to combat obesity. Mice that carry two defective variants of the gene encoding leptin have abnormal growth, have an unbridled appetite, and become obese. Furthermore, the receptors for leptin, unlike the receptors for hormones such as insulin, are primarily expressed in the brain in regions that control eating behavior, namely the hypothalamic arcuate nucleus and the hypothalamic paraventricular nucleus. Binding of leptin to its receptor, Ob-Rb, activates a JAK-STAT signaling pathway that leads to the activation of expression of the POMC gene and thus exerts anorexigenic effects. Despite the involvement of leptin in food intake, however, injection of the hormone is not associated with weight reduction.

This finding suggests that steps in energy homeostasis that are downstream of leptin expression, as well as other factors, also play key roles in obesity. The insulin hormone, produced by β-pancreatic cells, has receptors in many organs, including the hypothalamus. Similar to leptin, insulin signals for the increased production of POMC; insulin receptors in NPY neurons decrease the production of the orexigenic NPY. Unlike leptin and insulin, ghrelin stimulates orexigenic neurons. Also in contrast to leptin and insulin, this hormone produced by endocrine cells in the stomach acts on a short time scale and is responsible for rapid feelings of sharp hunger. In addition to these and other hormones, the melanocortin system is regulated by nutrients such as glucose, lipids, and amino acids. The interplay of neuroendocrine mediators has evolved to control food intake and metabolism, to prevent starvation, and to avoid harmful obesity.