Melanocortin 4 Receptors Reciprocally Regulate Sympathetic and Parasympathetic Preganglionic Neurons

Sohn, Jong Woo; Harris, Louise E.; Berglund, Eric D.; Liu, Tiemin; Vong, Linh; Lowell, Bradford B.; Balthasar, Nina; Williams, Kevin W.; Elmquist, Joel K.

doi:10.1016/j.cell.2012.12.022

Cited by 181 publications

(185 citation statements)

References 31 publications

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“…An increased overall SNS activity was evident in rats after the POMC-AAV administration into the NTS, which also fits with our finding (Zhang et al 2010). The inhibition of vagal activity via MC4R has been recently studied ex vivo using electrophysiology and reported to take place in the dorsal motor nucleus of the vagus (DMV) nerve, which receives POMC projections from the NTS (Sohn et al 2013). Our results show that the inhibition of vagal activity is evident in vivo and is sustained when a-MSH is overexpressed in the NTS neurons.…”

Section: Discussionsupporting

confidence: 78%

“…However, a-MSH has also been demonstrated to regulate insulin levels and glucose homeostasis independent of the changes in body weight via regulation of the autonomic nervous system (Obici et al 2001, Rossi et al 2011, Sohn et al 2013. Recent research using cell-specific genetic manipulation of Mc4r has demonstrated the key role of MC4R in the cholinergic neurons in inhibition of parasympathetic neurons and activation of sympathetic neurons leading to changes in energy, glucose, and cardiovascular homeostasis (Rossi et al 2011, Sohn et al 2013. Although the analysis of HR control by the autonomic nervous system showed an increased sympathetic tone and a decreased parasympathetic tone, it was not reflected to the longterm changes in insulin and glucose levels in this study.…”

Section: Discussionmentioning

confidence: 99%

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α-MSH overexpression in the nucleus tractus solitarius decreases fat mass and elevates heart rate

Eerola¹,

Rinne²,

Penttinen³

et al. 2014

Journal of Endocrinology

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The POMC pathway is involved in the regulation of energy and cardiovascular homeostasis in the hypothalamus and the brain stem. Although the acute effects of POMC-derived peptides in different brain locations have been elucidated, the chronic site-specific effects of distinct peptides remain to be studied. To this end, we used a lentiviral gene delivery vector to study the long-term effects of a-MSH in the nucleus tractus solitarius (NTS) of the brain stem. The a-MSH vector (LVi-a-MSH-EGFP) based on the N-terminal POMC sequence and a control vector (LVi-EGFP) were delivered into the NTS of C57BL/6N male mice fed on a western diet. Effects on body weight and composition, feeding, glucose metabolism, and hemodynamics by telemetric analyses were studied during the 12-week follow-up. The LVi-a-MSH-EGFP-treated mice had a significantly smaller gain in the fat mass compared with LVi-EGFP-injected mice. There was a small initial decrease in food intake and no differences in the physical activity. Glucose metabolism was not changed compared with the control. LVi-a-MSH-EGFP increased the heart rate (HR), which was attenuated by adrenergic blockade suggesting an increased sympathetic activity. Reduced response to muscarinic blockade suggested a decreased parasympathetic activity. Fitting with sympathetic activation, LVi-a-MSH-EGFP treatment reduced urine secretion. Thus, the results demonstrate that long-term a-MSH overexpression in the NTS attenuates diet-induced obesity. Modulation of autonomic nervous system tone increased the HR and most probably contributed to an anti-obesity effect. The results underline the key role of NTS in the a-MSH-induced long-term effects on adiposity and in regulation of sympathetic and parasympathetic activities.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

α-MSH overexpression in the nucleus tractus solitarius decreases fat mass and elevates heart rate

Eerola¹,

Rinne²,

Penttinen³

et al. 2014

Journal of Endocrinology

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“…However, the question of how the central insulin action actually controls the vagus nerve activity via hypothalamic neurons and suppresses HGP remains unanswered. HGP is also suppressed by icv administration of α-MSH [35], and according to a patch clamp study, the agonist of melanocortin receptor, which is the receptor of α-MSH, causes hyperpolarization of DMV neurons [36]. In addition, it has been revealed that diazoxide, which activates K ATP channel and induce hyperpolarization of neurons, suppresses HGP when administered to DMV [37].…”

Section: Central Insulin Action and The Vagus Nervementioning

confidence: 99%

Central insulin-mediated regulation of hepatic glucose production [Review]

Inoue

2016

Endocr J

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Abstract. Insulin controls hepatic glucose production (HGP) and maintains glucose homeostasis through the direct action of hepatic insulin receptors, as well as the indirect action of insulin receptors in the central nervous system. Insulin acts on insulin receptors in the hypothalamic arcuate nucleus, activates ATP-sensitive potassium channels in a phosphoinositide 3-kinase (PI3K)-dependent manner, induces hyperpolarization of the hypothalamic neurons, and regulates HGP via the vagus nerve. In the liver, central insulin action augments IL-6 expression in Kupffer cells and activates STAT3 transcription factors in hepatocytes. Activated STAT3 suppresses the gene expression of gluconeogenic enzymes, thereby reducing HGP. It has become evident that nutrients such as glucose, fatty acids, and amino acids act upon the hypothalamus together with insulin, affecting HGP. On the other hand, HGP control by central insulin action is impeded in obesity and impeded by insulin resistance due to disturbance of PI3K signaling and inflammation in the hypothalamus or inhibition of STAT3 signaling in the liver. Although the mechanism of control of hepatic gluconeogenic gene expression by central insulin action is conserved across species, its importance in human glucose metabolism has not been made entirely clear and its elucidation is anticipated in the future.Key words: Hypothalamus, Insulin, Liver, Vagus nerve, STAT3 THE LIVER plays a central role in the maintenance of whole-body glucose homeostasis, by adjusting glucose production according to the energy balance. The master regulator of hepatic glucose production (HGP) is insulin, as the liver is exposed to portal blood, which displays high insulin concentrations of approximately three times that in venous blood [1]. Indeed, in diabetes mellitus, the increase of HGP is closely related to the rise of fasting blood level [2]. HGP is strongly controlled by direct actions of insulin on hepatocytes [3]. When bound to its receptor, insulin suppresses HGP via the activation of phosphoinositide 3-kinase (PI3K) signal transduction pathway consisting of insulin receptor substrate (IRS), PI3K, phosphoinositide-dependent kinase 1 (PDK1) and Akt [4]. Thus, liver-specific insulin receptor knockout mice or impaired PI3K signal transduction exhibit hyperinsulinemia and glucose intolerance with impaired insulin-dependent suppression of HGP [5][6][7][8]. Meanwhile, insulin is known to control HGP not only by direct mechanisms via hepatic insulin receptors, but also by indirect mechanisms mediated by insulin actions on other organs (Fig.1). It has been reported that insulin still suppresses HGP partially even in mice with PI3K signal transduction inhibition in the liver [8,9]. Further, in an investigation of the changes in HGP after intravenous and intraportal insulin administration, it was shown that the differences in portal blood insulin level, that is, the direct insulin action on hepatocytes, do not necessarily correlate with the effect of insulin on HGP suppression [10].Indirect suppressio...

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“…MC4R has been associated with key components of nutrient absorption, lipid metabolism, energy expenditure, thermogenesis, adiposity, insulin secretion, food intake, and appetite (Adan et al 2006). Moreover, the MC pathway interacts with other key hormones or pathways such as leptin, 5-HT (Zhou et al 2007), NPY, AGRP, POMC (Biebermann et al 2012), and ANS (Rossi et al 2011;Sohn et al 2013) in the hypothalamus and brainstem (Loos 2011), GLP-1 pathway (Gautron et al 2010), CCK, and vagal afferent fibers (Guan et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults

et al. 2014

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Melanocortin 4 receptor (MC4R) has a major role in energy homeostasis. The rs17782313 polymorphism, mapped 188 kb downstream from MC4R, has been associated with satiety, higher body mass index (BMI) and total calorie intake in adults. To assess the association of rs17782313 with gastric functions, satiation, or satiety, we studied 178 predominantly Caucasian overweight and obese people: 120 females, 58 males; mean BMI 33.4 ± 5.3 kg/m 2 (SD); age 37.7 ± 11.2 years. Quantitative traits assessed were gastric emptying (GE) of solids and liquids; fasting and postprandial gastric volume; satiation by maximum tolerated volume and 4 symptoms by 100-mm visual analog scales (VAS); and satiety by ad libitum buffet meal. Associations of genotype and quantitative traits were assessed by analysis of covariance (using gender and BMI as covariates), based on a dominant [TC (n = 72) -CC (n = 12) vs. TT (n = 94)] genetic model. rs17782313(C) was associated with postprandial satiation symptoms (median D total VAS 26.5 mm, p = 0.036), reduced proportion of solid GE at 2 h (median D 6.7 %, p = 0.008) and 4 h (median D 3.2 %, p = 0.006), and longer t (median D 6 min, p = 0.034). Associations of rs17782313 with obesity may be explained by reduced satiation and GE. The role of MC4R mechanisms in satiation and gastric function deserves further study.

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Melanocortin 4 Receptors Reciprocally Regulate Sympathetic and Parasympathetic Preganglionic Neurons

Cited by 181 publications

References 31 publications

α-MSH overexpression in the nucleus tractus solitarius decreases fat mass and elevates heart rate

α-MSH overexpression in the nucleus tractus solitarius decreases fat mass and elevates heart rate

Central insulin-mediated regulation of hepatic glucose production [Review]

Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults

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