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The Mesencephalic Trigeminal Nucleus Controls Food Intake and Body Weight via Hindbrain POMC Projections.

ABSTRACT: The mesencephalic trigeminal nucleus (Mes5) processes oral sensory-motor information, but its role in the control of energy balance remains unexplored. Here, using fluorescent in situ hybridization, we show that the Mes5 expresses the melanocortin-4 receptor. Consistent with MC4R activation in other areas of the brain, we found that Mes5 microinjection of the MC4R agonist melanotan-II (MTII) suppresses food intake and body weight in the mouse. Furthermore, NTS POMC-projecting neurons to the Mes5 can be chemogenetically activated to drive a suppression in food intake. Taken together, these findings highlight the Mes5 as a novel target of melanocortinergic control of food intake and body weight regulation, although elucidating the endogenous role of this circuit requires future study. While we observed the sufficiency of Mes5 MC4Rs for food intake and body weight suppression, these receptors do not appear to be necessary for food intake or body weight control. Collectively, the data presented here support the functional relevance of the NTS POMC to Mes5 projection pathway as a novel circuit that can be targeted to modulate food intake and body weight.

SUBMITTER: Fortin SM

PROVIDER: S-EPMC8152732 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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The Mesencephalic Trigeminal Nucleus Controls Food Intake and Body Weight via Hindbrain POMC Projections.

Fortin Samantha M SM Chen Jack J Grill Harvey J HJ Hayes Matthew R MR

Nutrients 20210513 5

The mesencephalic trigeminal nucleus (Mes5) processes oral sensory-motor information, but its role in the control of energy balance remains unexplored. Here, using fluorescent in situ hybridization, we show that the Mes5 expresses the melanocortin-4 receptor. Consistent with MC4R activation in other areas of the brain, we found that Mes5 microinjection of the MC4R agonist melanotan-II (MTII) suppresses food intake and body weight in the mouse. Furthermore, NTS POMC-projecting neurons to the Mes5 ...[more]

PMID: 34068091

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Project description:Clinical imaging studies have revealed that the hypothalamus is activated in migraine patients prior to the onset of and during headache and have also shown that the hypothalamus has increased functional connectivity with the spinal trigeminal nucleus. The dopaminergic system of the hypothalamus plays an important role, and the dopamine-rich A11 nucleus may play an important role in migraine pathogenesis. We used intraperitoneal injections of glyceryl trinitrate to establish a model of acute migraine attack and chronicity in mice, which was verified by photophobia experiments and von Frey experiments. We explored the A11 nucleus and its downstream pathway using immunohistochemical staining and neuronal tracing techniques. During acute migraine attack and chronification, c-fos expression in GABAergic neurons in the A11 nucleus was significantly increased, and inhibition of DA neurons was achieved by binding to GABA A-type receptors on the surface of dopaminergic neurons in the A11 nucleus. However, the expression of tyrosine hydroxylase and glutamic acid decarboxylase proteins in the A11 nucleus of the hypothalamus did not change significantly. Specific destruction of dopaminergic neurons in the A11 nucleus of mice resulted in severe nociceptive sensitization and photophobic behavior. The expression levels of the D1 dopamine receptor and D2 dopamine receptor in the caudal part of the spinal trigeminal nucleus candalis of the chronic migraine model were increased. Skin nociceptive sensitization of mice was slowed by activation of the D2 dopamine receptor in SP5C, and activation of the D1 dopamine receptor reversed this behavioral change. GABAergic neurons in the A11 nucleus were activated and exerted postsynaptic inhibitory effects, which led to a decrease in the amount of DA secreted by the A11 nucleus in the spinal trigeminal nucleus candalis. The reduced DA bound preferentially to the D2 dopamine receptor, thus exerting a defensive effect against headache.

Project description:ObjectiveObesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing's Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11β-hydroxysteroid dehydrogenase type1 (11βHSD1), which increases the local concentration of active glucocorticoids by the production of corticosterone from 11-dehydrocorticosterone. 11βHSD1 is expressed in the hypothalamic arcuate nucleus (ARC), a major weight and appetite-regulating centre, and therefore represents a target for novel anti-obesity therapeutic agents. Thus, we sought to investigate the effect of chronic alterations of ARC corticosterone levels (mediated by 11βHSD1) on food intake and body weight in adult male rats.MethodsRecombinant adeno-associated virus particles bearing sense 11βHSD1 (rAAV-S11βHSD1) and small interfering 11βHSD1 (rAAV-si11βHSD1), respectively, were stereotactically injected into the ARC (bilaterally) of adult male Wistar rats. rAAV-GFP was injected into control groups of male Wistar rats. Food intake and body weight were measured three times a week for 70 days. Terminal brain, plasma and intrascapular brown adipose tissue (iBAT) samples were taken for measurement of mRNA expression and hormone levels.ResultsCompared to controls, rAAV-S11βHSD1 injection resulted in higher ARC corticosterone levels, hyperphagia and increased weight gain. Conversely, rAAV-si11βHSD1 injection (compared to controls) resulted in lower ARC corticosterone levels, higher iBAT uncoupling protein-1 mRNA expression and less weight gain despite similar food intake.ConclusionsTherefore ARC corticosterone, regulated by 11βHSD1, may play a role in food intake and body weight regulation. These data have important implications for the development of centrally-acting 11βHSD1 inhibitors, which are currently being developed for the treatment of obesity, metabolic disorders, and other conditions.

Dataset Information

The Mesencephalic Trigeminal Nucleus Controls Food Intake and Body Weight via Hindbrain POMC Projections.

Publications

The Mesencephalic Trigeminal Nucleus Controls Food Intake and Body Weight via Hindbrain POMC Projections.

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