Differential control of metabolic and cardiovascular functions by melanocortin-4 receptors in proopiomelanocortin neurons
Open accessAbstract
We examined the role of melanocortin-4 receptors (MC4R) in proopiomelanocortin (Pomc) neurons in regulating metabolic and cardiovascular functions. Using Cre-loxP technology, we selectively rescued MC4R in Pomc neurons of mice with whole body MC4R deficiency (MC4R-Pomc-Cre mice). Body weight, food intake, and whole body oxygen consumption (V̇o 2) were determined daily, and blood pressure (BP), heart rate (HR), and body temperature were measured 24 h/day by telemetry. An intracerebroventricular cannula was placed in the right lateral ventricle for intracerebroventricular infusions. Littermate MC4R-deficient (LoxTB-MC4R) mice were used as controls. After control measurements, the MC4R antagonist (SHU-9119; 1 nmol/h) was infused intracerebroventricularly for 7 days. Compared with LoxTB-MC4R mice, MC4R-Pomc-Cre mice were less obese (47 ± 2 vs. 52 ± 2 g) and had increased energy expenditure (2,174 ± 98 vs. 1,990 ± 68 ml·kg−1·min−1), but food intake (4.4 ± 0.2 vs. 4.3 ± 0.3 g/day), BP (112 ± 1 vs. 109 ± 3 mmHg), and HR [557 ± 9 vs. 551 ± 14 beats per minute (bpm)] were similar between groups. Chronic SHU-9119 infusion increased food intake (4.2 ± 0.2 to 6.1 ± 0.5 g/day) and body weight (47 ± 2 to 52 ± 2 g) in MC4R-Pomc-Cre mice, while no changes were observed in LoxTB-MC4R mice. Chronic SHU-9119 infusion also increased BP and HR by 5 ± 1 mmHg and 60 ± 8 bpm in MC4R-Pomc-Cre mice without altering BP or HR in LoxTB-MC4R mice. These results indicate that MC4Rs in Pomc neurons are important for regulation of energy balance. In contrast, while activation of MC4R in Pomc neurons facilitates the BP response to acute stress, our data do not support a major role of MC4R in Pomc neurons in regulating baseline BP and HR.
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These hormones and receptors influence the nucleus of the solitary tract and the arcuate nucleus of the hypothalamus, which can affect set points.
“They also have influences on the nucleus of the solitary tract (NTS) as well as the arcuate nucleus of the hypothalamus, which can affect set points (da Silva et al. 2014; do Carmo et al. 2013; Sohn et al. 2013; Speakman 2014).”
From Motion sickness: more than nausea and vomiting (2014) · cites this paper as do Carmo et al. 2013
The Abstract (page unavailable) locates POMC neurons in the arcuate nucleus, notes that the NTS also contains them, and describes melanocortin signaling as regulating appetite and energy expenditure. It says the physiological role of NTS POMC neurons is largely unknown, however, and does not establish that influences on both regions affect set points. (LLM, conf=0.84)
Experimental — accuracy not yet measuredActivation of MC4R might sensitize POMC neurons to other stimuli that influence sympathetic activity.
“In mice with defective MC4R signalling in the CNS, restoration of MC4R expression on POMC neurons partially restored BP responses to acute stress, suggesting that activation of MC4R might sensitize POMC neurons to other stimuli that influence sympathetic activity209.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [209]
In mice with defective MC4R signalling in the central nervous system, restoration of MC4R expression on POMC neurons partially restored blood pressure responses to acute stress.
“In mice with defective MC4R signalling in the CNS, restoration of MC4R expression on POMC neurons partially restored BP responses to acute stress, suggesting that activation of MC4R might sensitize POMC neurons to other stimuli that influence sympathetic activity209.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [209]
Rescuing MC4R function specifically in POMC neurons of mice with whole-body MC4R deficiency partially restored blood pressure responses to acute stress.
“Rescuing MC4R function specifically in POMC neurons of mice with whole-body MC4R deficiency partially restored BP responses to acute stress, suggesting that MC4R may serve to autopotentiate POMC neuronal activity [60].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [60]
MC4R may serve to autopotentiate POMC neuronal activity.
“Rescuing MC4R function specifically in POMC neurons of mice with whole-body MC4R deficiency partially restored BP responses to acute stress, suggesting that MC4R may serve to autopotentiate POMC neuronal activity [60].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [60]
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- Authors
- do Carmo, J. M., da Silva, A. A., Rushing, J. S., Pace, B., & Hall, J. E.
- Affiliations
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
- University of Mississippi Medical Center (US)
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2013-08-15
- Volume
- 305
- Issue
- 4
- Pages
- R359-R368
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- PMC
- PMC3833394
- OpenAlex
- W2078161791
- Cited by
- 38
- References
- 25
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 2 · 2021: 1 · 2020: 1 · 2019: 6 · 2018: 1 · 2017: 6 · 2016: 2 · 2015: 6 · 2014: 9 · 2013: 1
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Heart, Lung, and Blood Institute (P01-HL-51971, P01HL051971)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- melanocortin-4 receptor, proopiomelanocortin neurons, energy balance, obesity, dietary intake, energy expenditure, blood pressure, heart rate, cardiovascular function, hypothalamus, body temperature, oxygen consumption, neuroendocrine regulation of metabolism, neuroendocrine regulation of blood pressure, neuroendocrine regulation
- MeSH terms
- Uncoupling Protein 1, alpha-MSH, Animals, Blood Glucose, Blood Pressure, Body Temperature, Brain, Adipose Tissue, Brown, Eating, Energy Metabolism, Glucose Tolerance Test, Heart Rate, Hemodynamics, Ion Channels, Male, Mice, Transgenic, Melanocyte-Stimulating Hormones, Neurons, Oxygen Consumption, Peptides, Cyclic, Pro-Opiomelanocortin, Recombinant Fusion Proteins, Stress, Physiological, Telemetry, Time Factors, Weight Gain, Mice, Knockout, Monitoring, Ambulatory, Integrases, Mitochondrial Proteins, Receptor, Melanocortin, Type 4, Green Fluorescent Proteins, Intra-Abdominal Fat, Adiposity, Mice, Infusions, Intraventricular
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