Читать книгу The Science of Health Disparities Research - Группа авторов - Страница 31

Multiple nuclei within the hypothalamus are involved in complex gating and signaling that result from an intricate mixture of feedback and feed forward involving signals that originate in the complex neurotransmitter and neuroendocrine systems. Often, these interactions involve feedback communication amongst nuclei and signaling molecules from the periphery that indicate nutrient availability (Figure 2.3) [4, 5]. Following a meal, the two major harbingers of nutrient availability, leptin and insulin, play a major role in driving the signaling cascade in the hypothalamus (Figure 2.3) [10]. Elevation of blood glucose levels following a meal results in the activation and secretion of insulin from the beta‐islet cells of the pancreas. This occurs in concert with the leptin secretion from adipose tissue, which conveys the signal that energy is available for storage. The arcuate nucleus of the hypothalamus has receptors for both insulin and leptin and responds differently depending on which region of the arcuate receives input (Figure 2.3). Leptin and insulin repress signaling from neurons of the arcuate that produce the orexigenic agouti‐related peptide (AgRP) and neuropeptide Y (NPY), each of which functions to repress neurons in the PVN responsible for producing anorexigenic thyrotropin releasing hormone (TRH), and CRF. AgRP and NPY also stimulate neurons in the lateral hypothalamus (LH) that produce the orexigenic orexin and the orexigenic and anti‐thermogenic melanin concentrating hormone (MCH) [5, 11]. The net effect of leptin and insulin on AgRP‐ and NPY‐producing neurons is the repression of hunger. In contrast, the function of leptin and insulin on arcuate neurons is to stimulate the expression of anorexigenic pro‐opiomelanocortin (POMC) and cocaine and amphetamine regulated transcript (CART). POMC‐ and CART‐active neurons in the PVN express anorexigenic and thermogenic TRH and CRH, while repression neurons in the LH express orexigenic orexin and MCH. Therefore, in contrast to AgRP and NPY, POMC and CART repress hunger. Thus AgRP/NPY and POMC/CART have significant influence on modulating feeding, nutrient sensing, and the flux of signaling through the HPA axis [11, 12]. Finally, the hypothalamus is subject to modulation by local inflammatory events. Studies have shown that normal physiological control of feeding by the hypothalamus can be disrupted by local inflammation, some of which is influenced by high levels of dietary long chain fatty acids (LCFA) [4, 11]. This local inflammation blunts the response of the hypothalamus to leptin and insulin, thus implicating a role for inflammation in the evolution of obesity (Figure 2.3) [11].

Figure 2.3 Schematic representation of pathways important in hypothalamic control of energy balance and sleep. VLPO, ventrolaterol preoptic nucleus; DMH, dorsomedial hypothalamus; TRH, thyrotropin releasing hormone; CRF, corticotrophin releasing factor; PVN, paraventricular nucleus; SCN, suprachiasmic nucleus; LH, lateral hypothalamus; HPA, hypothalamus‐pituitary‐adrenal axis; AgRP, agouti‐related peptide; NPY, neuropeptide Y; POMC, pro‐opiomelanocortin; CART, cocaine and amphetamine related transcript; MCH, melanin‐concentrating hormone; TNF‐α, tumor necrosis factor alpha; IL1‐β, interleukin 1 beta; IL‐6, interleukin‐6; LCFA, long chain fatty acids.