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Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors - PubMed

Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors

Daniel D Lam et al. Endocrinology. 2008 Mar.

Abstract

The neurotransmitter serotonin (5-hydroxytryptamine) is a well-established modulator of energy balance. Both pharmacological and genetic evidence implicate the serotonin 2C receptor (5-HT(2C)R) as a critical receptor mediator of serotonin's effects on ingestive behavior. Here we characterized the effect of the novel and selective 5-HT(2C)R agonist BVT.X on energy balance in obese and lean mice and report that BVT.X significantly reduces acute food intake without altering locomotor activity or oxygen consumption. In an effort to elucidate the mechanism of this effect, we examined the chemical phenotype of 5-HT(2C)R-expressing neurons in a critical brain region affecting feeding behavior, the arcuate nucleus of the hypothalamus. We show that 5-HT(2C)Rs are coexpressed with neurons containing proopiomelanocortin, known to potently affect appetite, in the arcuate nucleus of the hypothalamus of the mouse. We then demonstrate that prolonged infusion with BVT.X in obese mice significantly increases Pomc mRNA and reduces body weight, percent body fat, and initial food intake. To evaluate the functional importance of melanocortin circuitry in the effect of BVT.X on ingestive behavior, we assessed mice with disrupted melanocortin pathways. We report that mice lacking the melanocortin 4 receptor are not responsive to BVT.X-induced hypophagia, demonstrating that melanocortins acting on melanocortin 4 receptor are a requisite downstream pathway for 5-HT(2C)R agonists to exert effects on food intake. The data presented here not only indicate that the novel 5-HT(2C)R agonist BVT.X warrants further investigation as a treatment for obesity but also elucidate specific neuronal pathways potently affecting energy balance through which 5-HT(2C)R agonists regulate ingestive behavior.

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Figures

Figure 1
Figure 1

BVT.X significantly reduces food intake. Effects of BVT.X on acute intake of HFD in DIO (n = 11, average body weight 53 g; A) and ob/ob (n = 6, average body weight 51 g; B) mice. Saline (SAL) or BVT.X (20 or 60 mg/kg) were administered ip 45 min before the onset of the dark cycle. Total food intake was measured 6 h after injection (mean ±

sem

). Significant differences are indicated as follows: **, P < 0.01; ***, P < 0.001.

Figure 2
Figure 2

5-HT2CRs are coexpressed with POMC in the ARC. A, Wild-type (+/+) mice exhibit endogenous POMC mRNA using ISHH with 35S-POMC (identified by clusters of black grains) but no β-galactosidase activity (X-gal stain of blue cytoplasm) in the ARC. B, Pomc tau-lacZ+/− mice display 35S-POMC in every neuron positive for X-gal. C, Higher level magnification of wild-type+/+ mouse ARC, showing 35S-POMC grains but no X-gal stain. D, Higher-level magnification of Pomc tau-lacZ+/− mouse ARC, showing a typical cell containing both 35S-POMC grains and X-gal stain (arrow). E–F, Fluorescent IHC for 5-HT2CR (E) and β-galactosidase (F) in Pomc tau-lacZ+/− mouse ARC. G, Merge of E and F, showing cells coexpressing 5-HT2CR and β-galactosidase (arrows). Scale bar (B), 200 μm and applies to A; (D), 20 μm and applies to C; (G), 20 μm and applies to E–G.

Figure 3
Figure 3

Prolonged 5-HT2CR agonist infusion increases POMC mRNA expression and reduces percent body fat, body weight, and initial food intake. Obese ob/ob mice (n = 8, mean body weight 46 g) were treated with saline or BVT.X (60 mg/kg·d for 7 d, sc minipump). A, Prolonged BVT.X treatment increased POMC mRNA in the ARC, compared with saline treatment, as determined by densitometry analysis after ISHH with a 35S-labeled antisense POMC riboprobe. Prolonged BVT.X treatment significantly decreased percent body fat as determined by DEXA (B) and body weight (grams) (C), compared with pretreatment levels. D, BVT.X treatment decreased chow pellet intake on d 1 and 2, but no further significant differences were observed. Data are presented as mean ±

sem

. Significant differences are indicated as follows: *, P < 0.05; **, P < 0.01.

Figure 4
Figure 4

BVT.X significantly decreases food intake in wild-type but not Mc4r null mice. Wild-type (A–C) and Mc4r null littermates (n = 9, average body weight 20 g) (D–F) received an acute injection of either saline or BVT.X (60 mg/kg, ip) and were assessed for 6 h in the CLAMS apparatus. BVT.X significantly reduced 6-h food intake (powdered chow) in wild-type mice (A) but not Mc4r null mice (D). BVT.X did not significantly affect average hourly locomotor activity (horizontal counts) (B and E) or VO2 (C and F) in either genotype. Data are presented as mean ±

sem

and significant differences are indicated: *, P < 0.05.

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