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Hypothalamic Neuronal Circuits Are Modulated by Insulin and Impact Metabolism 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Tadeu de Oliveira Diz, Sabela Casado, Rubén Nogueiras, Sulay Tovar
Insulin action over POMC neurons in the ARC stimulates the release of POMC peptide that is processed to generate α-melanocyte-stimulating hormone (α-MSH). This α-MSH activates second-order neurons through direct interaction with the melanocortin receptors (MCRs) which are part of the central melanocortin system, essential for the regulation of long-term energy homeostasis. The two main MCRs in the hypothalamus are melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R), they are G protein-coupled receptors with a high level of constitutive activity and play a critical role in mediating the anorexigenic signal through α-MSH and the orexigenic signal through AgRP, respectively (28, 47). The activation of MC4R by α-MSH signals decreases energy intake. Moreover, POMC neurons’ action over distinct MC4R expressing neuronal populations causes a decrease in insulin secretion or increases insulin sensitivity independently of their effect on food intake and energy expenditure (48).
Role of Mitochondrial Dysfunction in Human Obesity
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
David Albuquerque, Sara Carmo-Silva, Daniel Álvarez-Vaca, Célia Aveleira, Clévio Nóbrega
In a particular region of the hypothalamus, we can find the arcuate nucleus (ARC). Within this region, there are two distinct functionally antagonist types of neurons population that regulate food intake and energy expenditure (the orexigenic (hunger signaling) neuropeptine Y (NPY) and agouti-related peptide (AgRP)-expressing (NPY/AgRP) neurons, and the anorexigenic (satiety signaling) pro-opiomelanocortin (POMC)-expressing POMC neurons) (Timper and Brüning, 2017). Both of these neurons play an important role of the control circuits in ARC that regulate food intake and energy homeostasis. NPY neurons are activated by ghrelin release from the stomach, and inhibited by insulin and leptin after nutrient intake (Schwartz et al., 2013). Leptin deficiency in the fasting state or in ob/ob mice markedly elevates NPY mRNA. Leptin administration decreases the ARC NPY mRNA levels in ob/ob mice and fasted rodents (Elias et al., 1999). POMC is the precursor of alpha-melanocyte stimulating hormone (α-MSH), which decreases feeding by acting through its receptors melanocortin 3 receptor (MC3R) and MC4R, in response to insulin and leptin action (Schwartz et al., 2013). Obesity can impair this intricate neuronal network and deregulate food intake and energy expenditure processes.
Obesity Is a Major Health Problem: Causes and Natural History
Published in Susan L. McElroy, David B. Allison, George A. Bray, Obesity and Mental Disorders, 2006
A third defect results from mutations in the melanocortin receptor (51–53). Several forms of this receptor transmit signals for activation of the adrenal gland by ACTH (melanocortin 1-receptor), activation of the melanocyte (melanocortin 2-receptor), and suppression of food intake by α-MSH (melanocortin 3-receptor and melanocortin 4-receptor). Genetic engineering to eliminate the MC4R in the mouse brain produces massive obesity. Several reports claim a genetic defect in this receptor is the culprit in some humans with obesity. These individuals are of either sex and are massively obese. A much rarer form of human obesity has been reported when production of proopiomelanocortin (POMC), the precursor for peptides that act on the melanocortin receptors, is defective (54). These people have red hair, endocrine defects and are moderately obese.
Dopaminergic and other genes related to reward induced overeating, Bulimia, Anorexia Nervosa, and Binge eating
Published in Expert Review of Precision Medicine and Drug Development, 2022
Kenneth Blum, Panayotis K. Thanos, Gene -Jack Wang, Abdalla Bowirrat, Luis Llanos Gomez, David Baron, Rehan Jalali, Marjorie C Gondré-Lewis, Mark S Gold
Along with the dopamine D2 receptor, the melanocortin-3 receptor (MC3R) and MC4R play crucial roles in energy homeostasis. Interestingly, the ventral tegmental area (VTA) is one of the highest sites of MC3R expression. Lippert et al. demonstrated that the MC3R, but not MC4R, is expressed in up to a third of the VTA’s dopaminergic neurons. Global deletion of the MC3R increases total dopamine by 42% in the VTA and decreases sucrose intake and preference only in female mice. Ovariectomy restores dopamine levels to normal, but in prepubertal female mice have decreased VTA dopamine levels. Because arcuate Agouti-related peptide/neuropeptide Y neurons are known to innervate and regulate VTA signaling involved in eating behavior, the MC3R in dopaminergic neurons provides a specific input for communication of nutritional state within the mesolimbic dopamine system. This gender-specific effect supports a sexually dimorphic function of MC3R in regulating the mesolimbic dopaminergic system and reward and may also involve circulating estrogen [104].
Melanocortin 3 receptor gene polymorphism is associated with polycystic ovary syndrome in Turkish population
Published in Gynecological Endocrinology, 2019
Sema Hepsen, Erman Cakal, Melia Karakose, Nilnur Eyerci, Hanife Saat, Selvihan Beysel, Sanem Oztekin, Ferda Pinarli, Mesut Parlak
Melanocortin neuronal pathway is an important endpoint for the action of different mediators and especially leptin that secretes from adipocytes [11]. This pathway has a substantial effect on energy homeostasis and ingestive behaviors via primarily melanocortin 3 and 4 receptors with the hypothalamus and limbic system [12,13]. Studies concerned about melanocortin 3 gene in literature limited a few rat experiments and human studies. Melanocortin 3 receptor (MC3R) gene deficiency determined by an increase in adipose tissue in a rat experiment [14]. A mice study demonstrated that MC3R knock out may provoke insulin resistance during the taking of high-fat diet [15]. Up till to today; various MC3R gene polymorphisms were labored in different studies; the close linkage with Thyr6Lys and Val81Ile polymorphisms and obesity were elucidated [16,17]. We aimed to make a contribution to the genetic baseline of PCOS by investigating Thr6Lys (rs 3746619) and Val81Ile (rs 3827103) single nucleotide polymorphisms (SNPs) of MC3R due to the close relation of this syndrome with insulin resistance and obesity. As far as we know; this case and control study is the first one in literature revealing the possible association between melanocortin 3 receptor gene polymorphisms and PCOS.