MCH Neuron Activity Is Sufficient for Reward and Reinforces Feeding

2019 ◽  
Vol 110 (3-4) ◽  
pp. 258-270 ◽  
Author(s):  
Pelin Dilsiz ◽  
Iltan Aklan ◽  
Nilufer Sayar Atasoy ◽  
Yavuz Yavuz ◽  
Gizem Filiz ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Glucose Tolerance ◽  
Energy Homeostasis ◽  
Neuron Activity ◽  
Physiological Effects ◽  
Short Term ◽  
Direct Role ◽  
Reward Function ◽  
Melanin Concentrating Hormone

Background: Melanin-concentrating hormone (MCH)-expressing neurons have been implicated in regulation of energy homeostasis and reward, yet the role of their electrical activity in short-term appetite and reward modulation has not been fully understood. Objectives: We investigated short-term behavioral and physiological effects of MCH neuron activity manipulations. Methods: We used optogenetic and chemogenetic approaches in Pmch-cre transgenic mice to acutely stimulate/inhibit MCH neuronal activity while probing feeding, locomotor activity, anxiety-like behaviors, glucose homeostasis, and reward. Results: MCH neuron activity is neither required nor sufficient for short-term appetite unless stimulation is temporally paired with consumption. MCH neuronal activation does not affect short-term locomotor activity, but inhibition improves glucose tolerance and is mildly anxiolytic. Finally, using two different operant tasks, we showed that activation of MCH neurons alone is sufficient to induce reward. Conclusions: Our results confirm diverse behavioral/physiological functions of MCH neurons and suggest a direct role in reward function.

Neurotensin Enhances Locomotor Activity and Arousal and Inhibits Melanin-Concentrating Hormone Signaling

2019 ◽  
Vol 110 (1-2) ◽  
pp. 35-49 ◽  
Author(s):  
Talia Levitas-Djerbi ◽  
Dana Sagi ◽  
Ilana Lebenthal-Loinger ◽  
Tali Lerer-Goldshtein ◽  
Lior Appelbaum
Keyword(s):  
Locomotor Activity ◽  
Hormone Receptor ◽  
Behavioral Response ◽  
Hormone Signaling ◽  
Wild Type ◽  
Expression Levels ◽  
Physiological Processes ◽  
Melanin Concentrating Hormone ◽  
Behavioral Assays

Background: Hypothalamic neurotensin (Nts)-secreting neurons regulate fundamental physiological processes including metabolism and feeding. However, the role of Nts in modulation of locomotor activity, sleep, and arousal is unclear. We previously identified and characterized Nts neurons in the zebrafish hypothalamus. Materials and Methods: In order to study the role of Nts, nts mutant (nts–/–), and overexpressing zebrafish were generated. Results: The expression of both nts mRNA and Nts protein was reduced during the night in wild-type zebrafish. Behavioral assays revealed that locomotor activity was decreased during both day and night, while sleep was increased exclusively during the nighttime in nts–/– larvae. Likewise, inducible overexpression of Nts increased arousal in hsp70:Gal4/uas:Nts larvae. Furthermore, the behavioral response to light-to-dark transitions was reduced in nts–/– larvae. In order to elucidate potential contenders that may mediate Nts action on these behaviors, we profiled the transcriptome of 6 dpf nts–/– larvae. Among other genes, the expression levels of melanin-concentrating hormone receptor 1b were increased in nts–/– larvae. Furthermore, a portion of promelanin-concentrating hormone 1 (pmch1) and pmch2 neurons expressed the nts receptor. In addition, expression of the the two zebrafish melanin-concentrating hormone (Mch) orthologs, Mch1 and Mch2, was increased in nts–/– larvae. Conclusion: These results show that the Nts and Mch systems interact and modulate locomotor activity and arousal.

scholarly journals Melanin-concentrating hormone in peripheral circulation in the human

2017 ◽  
Vol 232 (3) ◽  
pp. 513-523 ◽  
Author(s):  
J Naufahu ◽  
F Alzaid ◽  
M Fiuza Brito ◽  
B Doslikova ◽  
T Valencia ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Reference Range ◽  
Resting Metabolic Rate ◽  
Peripheral Circulation ◽  
Reference Ranges ◽  
Older Individuals ◽  
Rp Hplc ◽  
Melanin Concentrating Hormone ◽  
Males And Females

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide with a well-characterised role in energy homeostasis and emergent roles in diverse physiologic functions such as arousal, mood and reproduction. Work to date has predominantly focused on its hypothalamic functions using animal models; however, little attention has been paid to its role in circulation in humans. The aims of this study were to (a) develop a radioimmunoassay for the detection of MCH in human plasma; (b) establish reference ranges for circulating MCH and (c) characterise the pattern of expression of circulating MCH in humans. A sensitive and specific RIA was developed and cross-validated by RP-HPLC and MS. The effective range was 19.5–1248 pg MCH/mL. Blood samples from 231 subjects were taken to establish a reference range of 19.5–55.4 pg/mL for fasting MCH concentrations. There were no significant differences between male and female fasting MCH concentrations; however, there were correlations between MCH concentrations and BMI in males and females with excess fat (P < 0.001 and P = 0.020) and between MCH concentrations and fat mass in females with excess fat (P = 0.038). Plasma MCH concentrations rose significantly after feeding in a group of older individuals (n = 50, males P = 0.006, females P = 0.023). There were no robust significant correlations between fasting or post-prandial MCH and resting metabolic rate, plasma glucose, insulin or leptin concentrations although there were correlations between circulating MCH and leptin concentrations in older individuals (P = 0.029). These results indicate that the role of circulating MCH may not be reflective of its regulatory hypothalamic role.

Chronic intracerebroventricular infusion of MCH causes obesity in mice

2003 ◽  
Vol 284 (3) ◽  
pp. E583-E588 ◽  
Author(s):  
Akira Gomori ◽  
Akane Ishihara ◽  
Masahiko Ito ◽  
Satoshi Mashiko ◽  
Hiroko Matsushita ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Control ◽  
Energy Homeostasis ◽  
The Body ◽  
Intracerebroventricular Infusion ◽  
Melanin Concentrating Hormone ◽  
Important Regulator ◽  
Obesity In Mice ◽  
Body Weight Control

Melanin-concentrating hormone (MCH) is a cyclic amino acid neuropeptide localized in the lateral hypothalamus. Although MCH is thought to be an important regulator of feeding behavior, the involvement of this peptide in body weight control has been unclear. To examine the role of MCH in the development of obesity, we assessed the effect of chronic intracerebroventricular infusion of MCH in C57BL/6J mice that were fed with regular or moderately high-fat (MHF) diets. Intracerebroventricular infusion of MCH (10 μg/day for 14 days) caused a slight but significant increase in body weight in mice maintained on the regular diet. In the MHF diet-fed mice, MCH more clearly increased the body weight accompanied by a sustained hyperphagia and significant increase in fat and liver weights. Plasma glucose, insulin, and leptin levels were also increased in the MCH-treated mice fed the MHF diet. These results suggest that chronic stimulation of the brain MCH system causes obesity in mice and imply that MCH may have a major role in energy homeostasis.

scholarly journals Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-Induced Weight Gain in Male Mice

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2596
Author(s):  
E. Matthew Morris ◽  
Roberto D. Noland ◽  
Michael E. Ponte ◽  
Michelle L. Montonye ◽  
Julie A. Christianson ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Weight Gain ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Energy Homeostasis ◽  
Chemical Reduction ◽  
Acid Oxidation ◽  
Short Term ◽  
Mitochondrial Fatty Acid

The central integration of peripheral neural signals is one mechanism by which systemic energy homeostasis is regulated. Previously, increased acute food intake following the chemical reduction of hepatic fatty acid oxidation and ATP levels was prevented by common hepatic branch vagotomy (HBV). However, possible offsite actions of the chemical compounds confound the precise role of liver energy metabolism. Herein, we used a hepatocyte PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy metabolism in systemic energy homeostasis. LPGC1a male, but not female, mice had a 70% greater high-fat/high-sucrose (HFHS) diet-induced weight gain compared to wildtype (WT) mice (p < 0.05). The greater weight gain was associated with altered feeding behavior and lower activity energy expenditure during the HFHS diet in LPGC1a males. WT and LPGC1a mice underwent sham surgery or HBV to assess whether vagal signaling was involved in the HFHS-induced weight gain of male LPGC1a mice. HBV increased HFHS-induced weight gain (85%, p < 0.05) in male WT mice, but not LPGC1a mice. These data demonstrate a sex-specific role of reduced liver energy metabolism in acute diet-induced weight gain, and the need for a more nuanced assessment of the role of vagal signaling in short-term diet-induced weight gain.

scholarly journals Central α-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Taylor Landry ◽  
Brenton Thomas Laing ◽  
Peixin Li ◽  
Wyatt Bunner ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Homeostasis ◽  
Ex Vivo ◽  
Immunohistochemical Analysis ◽  
Neuron Activity ◽  
Therapeutic Effects ◽  
Type I ◽  
Downstream Signaling ◽  
Reduced Body

α-Klotho is a circulating factor with well-documented anti-aging properties; however, the central role of α-klotho in metabolism remains largely unexplored. The current study investigated the potential role of central α-klotho to modulate NPY/AgRP neurons, energy balance, and glucose homeostasis. Intracerebroventricular (ICV) administration of α-klotho suppressed food intake, improved glucose profiles, and reduced body weight in mouse models of Type I and II diabetes. Furthermore, central α-klotho inhibition via an anti-α-klotho antibody impaired glucose tolerance. <i>Ex vivo</i> patch clamp electrophysiology and immunohistochemical analysis revealed that α-klotho suppresses NPY/AgRP neuron activity, at least in part, by enhancing mIPSC’s. Experiments in hypothalamic GT1-7 cells observed α-klotho induces phosphorylation of AKT<sup>ser473</sup>, ERK<sup>thr202/tyr204</sup>, and FOXO1<sup>ser256</sup>, as well as blunts AgRP gene transcription. Mechanistically, fibroblast growth factor 1 (FGFR1) inhibition abolished the downstream signaling of α-klotho, negated its ability to modulate NPY/AgRP neurons, and blunted its therapeutic effects. PI3 kinase inhibition also abolished α-klotho’s ability to suppress food intake and improve glucose clearance. These results indicate a prominent role of hypothalamic α-klotho/FGFR1/PI3K signaling in the modulation of NPY/AgRP neuron activity and maintenance of energy homeostasis, thus providing new insight into the pathophysiology of metabolic disease.

Abstract 074: Endothelial Caveolin-1 Mediates The Effects Of Dietary Sodium On Cardiovascular And Metabolic Function

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Fatthy Abidin ◽  
Amanda E Garza ◽  
Elijah Trefts ◽  
Jose R Romero ◽  
Gail K Adler ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Transmembrane Protein ◽  
Fasting Blood Glucose ◽  
Dietary Sodium ◽  
Metabolic Function ◽  
Fasting Insulin ◽  
Direct Role ◽  
High Sodium ◽  
Caveolin 1

Hypertension and insulin resistance (IR) are often associated with endothelial dysfunction; however, the underpinnings of their association are not well understood. Caveolin-1 (cav1) is a transmembrane protein identified in many cell types including cardiovascular (CV) and adipose cells. Our recent findings in mice and humans consistently suggest a role of cav1 in IR, dyslipidemia, CV dysfunction and hypertension in response to sodium loading. While adipose cav1 has been established as a critical mediator of glucose and lipid homeostasis, the role of endothelial cav1 in cardiometabolic dysfunction , and its relationship with dietary sodium is unclear. To test whether the cav1 in the endothelium mediates the effect of dietary sodium on CV and metabolic function, we used the Cre- loxP technology to generate a novel, endothelium-specific cav1 KO mouse model (Ecav1 KO). Glucose tolerance, BP, fasting insulin, lipids and the state of circulating RAAS were measured in Ecav1 KO and WT mice studied on low- and high-sodium diets (0.03 vs 1.6% Na) for 7 days. Ecav1 KO and WT mice had similar BW, food and water intake and urinary output on either diet. Compared to the WT, Ecav1 KO animals had significantly higher fasting blood glucose levels on a LS diet (103±4 vs 87±3 mg/dl, p<0.01) but not on a HS diet. Ecav1 KO mice also had impaired glucose tolerance vs the WT, especially on a HS diet; however, the glucose intolerance was not as pronounced in the Ecav1 KO as in the full cav1 KO. There were no differences in fasting insulin or lipid levels between the genotypes. On a HS diet, Ecav1 KO vs WT mice had significantly higher SBP levels (117±2 vs 109±3 mmHg, p<0.05). In addition, they had significantly higher pulse pressure (38±2 vs 29±1 mmHg, p<0.01), heart rates (802±11 vs 725±12 bpm, p<0.01) and rate pressure products, consistent with increased arterial stiffness and myocardial workload. These changes could not be explained by differences in kidney function; however, aldosterone levels were increased in Ecav1 KO vs WT animals (74±11 vs 48±5 ng/dl) despite no changes in PRA. Our findings are consistent with a direct role of endothelial cav1 in the development of IR and CV dysfunction, and highlight the importance of endothelial function in cardiometabolic homeostasis.

Mice with MCH ablation resist diet-induced obesity through strain-specific mechanisms

2005 ◽  
Vol 289 (1) ◽  
pp. R117-R124 ◽  
Author(s):  
Efi Kokkotou ◽  
Justin Y. Jeon ◽  
Xiaomei Wang ◽  
Francis E. Marino ◽  
Michael Carlson ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Energy Balance ◽  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Relative Increase ◽  
Potential Interaction ◽  
Mouse Strains ◽  
Genetic Ablation ◽  
Melanin Concentrating Hormone ◽  
Different Strains

Genetics and environment contribute to the development of obesity, in both humans and rodents. However, the potential interaction between genes important in energy balance, strain background, and dietary environment has been only minimally explored. We investigated the effects of genetic ablation of melanin-concentrating hormone (MCH), a neuropeptide with a key role in energy balance, with chow and a high-fat diet (HFD) in two different mouse strains, one obesity-prone (C57BL/6) and the other obesity-resistant (129). Substantial differences were seen in wild-type (WT) animals of different strains. 129 animals had significantly lower levels of spontaneous locomotor activity than C57BL/6; however, 129 mice gained less weight on both chow and HFD. In both strains, deletion of MCH led to attenuated weight gain compared with WT counterparts, an effect secondary to increased energy expenditure. In both strains, feeding a HFD led to further increases in energy expenditure in both WT and MCH-KO mice; however, this increase was more pronounced in 129 mice. In addition, mice lacking MCH have a phenotype of increased locomotor activity, an effect also seen in both strains. The relative increase in activity in MCH−/− mice is modest in animals fed chow but increases substantially when animals are placed on HFD. These studies reinforce the important role of MCH in energy homeostasis and indicate that MCH is a plausible target for antiobesity therapy.

scholarly journals Central α-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Taylor Landry ◽  
Brenton Thomas Laing ◽  
Peixin Li ◽  
Wyatt Bunner ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Homeostasis ◽  
Ex Vivo ◽  
Immunohistochemical Analysis ◽  
Neuron Activity ◽  
Therapeutic Effects ◽  
Type I ◽  
Downstream Signaling ◽  
Reduced Body

α-Klotho is a circulating factor with well-documented anti-aging properties; however, the central role of α-klotho in metabolism remains largely unexplored. The current study investigated the potential role of central α-klotho to modulate NPY/AgRP neurons, energy balance, and glucose homeostasis. Intracerebroventricular (ICV) administration of α-klotho suppressed food intake, improved glucose profiles, and reduced body weight in mouse models of Type I and II diabetes. Furthermore, central α-klotho inhibition via an anti-α-klotho antibody impaired glucose tolerance. <i>Ex vivo</i> patch clamp electrophysiology and immunohistochemical analysis revealed that α-klotho suppresses NPY/AgRP neuron activity, at least in part, by enhancing mIPSC’s. Experiments in hypothalamic GT1-7 cells observed α-klotho induces phosphorylation of AKT<sup>ser473</sup>, ERK<sup>thr202/tyr204</sup>, and FOXO1<sup>ser256</sup>, as well as blunts AgRP gene transcription. Mechanistically, fibroblast growth factor 1 (FGFR1) inhibition abolished the downstream signaling of α-klotho, negated its ability to modulate NPY/AgRP neurons, and blunted its therapeutic effects. PI3 kinase inhibition also abolished α-klotho’s ability to suppress food intake and improve glucose clearance. These results indicate a prominent role of hypothalamic α-klotho/FGFR1/PI3K signaling in the modulation of NPY/AgRP neuron activity and maintenance of energy homeostasis, thus providing new insight into the pathophysiology of metabolic disease.

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