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.

Keywords: MC4R; melanocortin; obesity.

Figure 1

Fluorescence in-situ hybridization images demonstrating expression of the MC4R on Mes5 neurons. Colocalization indicates expression of the MC4R (yellow) on Mes5 parvalbumin-expressing neurons (magenta) that border the dopamine beta-hydroxylase-expressing neurons (green) of the locus coeruleus. 4V = fourth ventricle, scp = superior cerebellar peduncle. Image corresponds to plate level 76 of Paxinos and Watson’s Mouse Brain Atlas, fourth edition.

Figure 2

Pharmacological activation of Mes5 MC4Rs suppresses food intake and body weight in male and female mice. (A,B) Bilateral Mes5 infusion of the MC3/4R agonist MTII (0.05 nmol) suppresses cumulative chow intake at 3, 6, and 24 h post-manipulation and (C,D) 24 h body weight change relative to vehicle treatment in male and female mice. Data represent means ±SEM; Paired Student’s t-tests: * = p < 0.05, ** = p < 0.01, *** = p < 0.001; n = 14 males, n = 9 females.

Figure 3

The Mes5 MC4R is not necessary for food intake or body weight control. Bilateral Mes5 infusion of the MC3/4R antagonist SHU9119 (60 pmol) does not impact cumulative chow intake in male (A) or female (B) mice. 24 h body weight is also not impacted by Mes5 directed infusion of SHU9119 in male ((C); n = 12) or female ((D); n = 8) mice. Cumulative 48-hr chow intake (E) and body weight (F) over 16 days is similar for Mes5 MC4R knockout (AAV-Cre-GFP; n = 11) and control (AAV-GFP; n = 7) mice. Data represent means ± SEM; Paired Student’s t-tests.

Figure 4

Chemogenic activation of NTS POMC projections acutely suppresses food intake. (A) In NTS^hM3Dq male, but not NTS^mCherry control male mice, injection of CNO (1 mg/kg; IP) suppresses 3 and 6 h cumulative chow intake but not 1 or 24 h food intake or (B) 24 h body weight change relative to vehicle treatment. (C) In NTS^hM3Dq female, but not NTS^mCherry control female mice, CNO suppresses 3 and 6 h chow intake but not 1 or 24 h food intake or (D) 24 h body weight change relative to vehicle treatment. All data represent means ± SEM; Paired Student’s t-tests: * = p < 0.05, ** = p < 0.01; n = 10 male NTS^hM3Dq and n = 7 male NTS^mCherry, n = 11 female NTS^hM3Dq and n = 5 female NTS^mCherry.

Figure 5

Chemogenic activation of NTS POMC projections to the Mes5 acutely suppresses food intake. (A) In NTS^hM3Dq mice, but not NTS^mCherry control mice, injection of CNO (1 mM) into the bilateral Mes5 suppresses 1, 3, and 6 h cumulative chow intake but not 24 h food intake in NTS or (B) 24 h body weight change relative to vehicle treatment. All data represent means ± SEM; Paired Student’s t-tests: * = p < 0.05; n = 9 NTS^hM3Dq and n = 9 NTS^mCherry.