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Neuropeptide Regulation of Ion Channels and Food Intake
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
In the brain, a large number of neuropeptide-expressing neurons participate in the control of food intake through sensing peripheral satiety and energy signals from the gut and adipose tissue. Some of these neuropeptide neurons belong to the first-order neurons that are directly modulated by peripherally released hormones such as ghrelin, leptin, and insulin (Balthasar et al. 2004). The typical representatives are neuropeptide-expressing neurons in the arcuate nucleus of the hypothalamus including agouti-related protein (AgRP) and proopiomelanocortin (POMC) neurons. However, many other neurons may receive information from the first-order neurons in the arcuate nucleus rather than a direct control by hormones secreted by gut and adipose tissue. The second-order neurons typically include oxytocin neurons in the paraventricular nucleus of the hypothalamus and melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus. In addition to the hypothalamus, the caudal brainstem, especially the nucleus of the solitary tract, is also a region with neurons that produce neuropeptides including glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) for satiety control. Although these neuropeptide-expressing neurons are located in separated brain areas, they work together via long-distance neural circuit connections to integrate satiety or hunger signals to the brain’s motivation center for the control of food intake.
Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
Recently, a human gene, located on Chromosome 16q22, was identified and named agouti-related transcript (Agrt; Art)153 or agouti-related protein (Agrp),168 because of its similarity to Agouti. This gene encodes a 132 amino acid protein that is 25% identical to human agouti, the highest degree of identity residing within the C-terminus. The murine homologue is a 131 amino acid protein and 81% identical to the human version. The gene is expressed primarily in the adrenal (cortex and medulla), subthalamic nucleus, and hypothalamus in both human and mouse,153,168 with low-level expression in the testis, lung, and kidney. Although the function of the gene product is at present unclear, it is a selective antagonist of MC-4R, is concentrated in the ARN and median eminence, and there is a tenfold upregulation in the hypothalamus of ob and db mice. This protein is therefore probably important in feeding, and may act via MC receptors. The fact that Bardet-Biedl syndrome maps near to this locus (16q21) may also be of significance.153 Overexpression of Art protein in transgenic mice resulted in weight gain, increased circulating insulin, delayed hyperglycemia, but no change in coat color.168,169 Hypertrophic adipose tissue and pancreatic islets were also evident.
Energy Metabolism and Appetite Control
Published in Ruth B.S. Harris, Appetite and Food Intake, 2017
Mark Hopkins, John E. Blundell
There is now considerable experimental data to support the view that leptin affects many central structures known to be involved in the neural control of food intake (Sainsbury and Zhang 2010), and it is commonly accepted that leptin is a signal that conveys information from the periphery to the brain regarding the long-term state of the body’s energy stores (Badman and Flier 2005, Morton et al. 2006, Woods and Ramsay 2011). Based on animal and in vitro molecular studies, changes to circulating leptin concentrations are thought to alter the hypothalamic expression of anorexigenic and orexigenic neuropeptide effector molecules, which promote corrective responses in energy intake (EI) and expenditure to minimize perturbation to energy balance (Morton et al. 2006). For example, a reduction in leptin is thought to promote increased motivation to eat via a down-regulation in the hypothalamic expression of anorexigenic neuropeptides such as proopiomelanocortin (POMC) and alpha melanocyte-stimulating hormone (α-MSH) and an up-regulation in the expression of orexigenic neuropeptides such as neuropeptide Y (NPY) and agouti-related protein (AgRP) (Lenard and Berthoud 2008, Sainsbury and Zhang 2010). As a consequence, leptin is now viewed as central to the hypothalamic control of energy homeostasis and has become inextricably linked with support for the lipostatic theory of appetite control. Indeed, it has been suggested that EI and energy expenditure are actually controlled in the interests of regulating body weight and, specifically, fat mass (FM) (Rosen and Spiegelman 2006), with leptin central to this coordination. This approach has encouraged the view that adipose tissue is the main driver of day-to-day food intake (Badman and Flier 2005, Morton et al. 2006, Woods and Ramsay 2011).
Adiponectin and resistin in acutely ill and weight-recovered adolescent anorexia nervosa: Association with psychiatric symptoms
Published in The World Journal of Biological Psychiatry, 2019
Marta Tyszkiewicz-Nwafor, Agnieszka Slopien, Monika Dmitrzak-Węglarz, Filip Rybakowski
Resistin, aptly named for its ability to induce insulin resistance, is a 12.5-kDa protein containing 114 amino acids, and is encoded by the gene on chromosome 19. Its structure resembles adiponectin, as well as proteins involved in inflammatory processes (Banerjee and Lazar 2003). In humans, it is secreted mainly by pre-adipocytes and also by the stromovascular fraction of adipose tissue and peripheral blood monocytes (Patel et al. 2003). It has been observed that, similar to leptin, resistin concentrations are higher in women, decrease during fasting periods and increase after refeeding, but these findings have not been confirmed in other studies. Animal studies demonstrate that injection of recombinant resistin increases blood glucose and insulin concentrations, and reduces glucose tolerance and insulin action. Neutralization with anti-resistin antibodies decreases blood glucose and improves insulin action (Meier and Gressner 2004). Resistin inhibits adipogenesis, whereas the loss of resistin function increases body weight and fat. Thus, resistin plays a significant role in energy and glucose homeostasis. Moreover, resistin expression has been detected in mouse brain, particularly the arcuate nucleus of the hypothalamus and the pituitary gland. Intracerebroventricular resistin treatment increases the expression of neuropeptide Y and agouti-related protein, which stimulates appetite and inhibits energy expenditure. In animal models, it has been demonstrated that resistin may affect dopaminergic and noradrenergic neurotransmission and affect the autonomic nervous system (Brunetti et al. 2004).
Sex-dependent effects of MC4R genotype on HPA axis tone: implications for stress-associated cardiometabolic disease
Published in Stress, 2019
Aki T-B. Chaffin, Yanbin Fang, Karlton R. Larson, Joram D. Mul, Karen K. Ryan
The MC4R is a G protein-coupled receptor expressed widely in the adult central nervous system (Cone, 2005; Tao, 2010). Its activity is coordinated by opposing actions of its endogenous agonist, αMSH, and its endogenous antagonist, agouti-related protein (AgRP) (Fong et al., 1997; Ollmann et al., 1997; Shutter et al., 1997). In addition, the receptor has intrinsic constitutive activity on which AgRP can act as an inverse agonist (Srinivasan et al., 2004). αMSH producing neurons in the arcuate nucleus of the hypothalamus are activated by restraint stress (Liu et al., 2007) and provide melanocortinergic input to MC4R-expressing neurons in key stress and feeding-regulatory brain regions including the paraventricular nucleus of the hypothalamus (PVN), the medial amygdala (MeA), and the nucleus accumbens (NAc) (Balthasar, 2006; Wang et al., 2015). Activation of MC4Rs by αMSH or pharmacological agonists acutely stimulates the HPA axis in male rats and mice (Liu et al., 2013) and induces weight loss by reducing caloric intake and increasing energy expenditure in both sexes (Fan et al., 1997; Hamilton & Doods, 2002). Conversely, loss of MC4R function (Ryan et al., 2014) or its pharmacological blockade (Kokare et al., 2010; Liu et al., 2007; Serova et al., 2013) blunts acute restraint stress-induced corticosterone elevation in male rats and mice. MC4R loss-of-function also induces weight gain by increasing caloric intake and decreasing energy expenditure in both sexes (Huszar et al., 1997). Our results (Figure 4) are consistent with these reports.
Understanding the impact of commonly utilized, non-insulin, glucose-lowering drugs on body weight in patients with type 2 diabetes
Published in Expert Opinion on Pharmacotherapy, 2018
Kathryn M. Hurren, Marissa W. Dunham
The mechanism for weight loss related to metformin is impacted significantly by effects on the central nervous system (CNS). Metformin likely crosses the blood brain barrier, and is proposed to exert direct effects on the hypothalamus through decreases in neuropeptide-Y and agouti-related protein, ultimately reducing appetite and food intake while total daily energy expenditure remains unaffected [20]. Reducing insulin resistance in the brain also serves to further decrease adenosine monophosphate kinase (AMPK) and increase pro-opiomelanocortin which reduces food cravings. Metformin improves leptin sensitivity and reduces its secretion, and subsequently reduces AMPK activity in the hypothalamus. In vitro, metformin directly inhibits production of the orexigenic hormone ghrelin through AMPK in rat gastric cells [26].