Differential effects of monoamine reuptake inhibitors on food intake and energy expenditure in a mouse model of diet‐induced obesity

Abstract

Dopamine (DA), norepinephrine (NE) and serotonin (5‐HT) modulate feeding behavior and energy homeostasis. Here, we investigated effects of sibutramine (Sib), duloxetine (Dlx), and atomoxetine (Atx) on acute food intake (FI), daily FI and body weight (BW) gain over 28 d in diet‐induced obese (DIO) mice. Sib is a balanced reuptake inhibitor at transporters for DA (DAT), 5‐HT (SERT) and NE (NET), whereas Dlx and Atx are selective for SERT and NET, respectively. Mice, fed a high fat diet for 12 wk, weighed 40–44 g prior to receiving chronic twice daily oral dosing for 28 d. FI, BW, serum leptin levels and weight of adipose tissue were measured and compared to free concentrations of compounds in serum and brain. Sib (1–10 mg/kg), Dlx (3–30 mg/kg) and Atx (3–30 mg/kg) dose‐dependently decreased food intake 4 and 8 hr after a single dose (hypophagia rank order of potency: Sib = Dlx > Atx). From 7 – 28 d, daily FI was equivalent in all groups of mice. At the highest doses tested, BW decreased significantly in Sib‐ and Atx‐treated mice at day 28 (~10% compared to vehicle), whereas BW was unchanged by the end of chronic Dlx treatment. On day 29, all compounds decreased serum leptin levels. Atx‐induced decrease in BW was accompanied by a reduction in total brown adipose tissue. These results suggest that the balance of activity at DAT, SERT and NET differentially influences acute hypophagia, energy expenditure and sustained weight loss.