Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Abstract

Bupropion (BUP) is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor that causes mild weight loss in obese adults. Subchronic (7 day) coadministration of selective DA and NE reuptake inhibitors also causes weight loss in mice. Because weight loss was not associated with decreased caloric intake, subchronic BUP might cause weight loss through increased energy expenditure. Acute studies demonstrate that BUP or DA + NE reuptake inhibitors cause transient hypophagia and increased locomotion; though the effects on temperature are inconsistent. Because subchronic DA + NE reuptake inhibition does not affect appetite, there is clearly a difference between the acute and subchronic effects of DA + NE reuptake inhibitors; however the effects of chronic (or subchronic) BUP on energy balance have never been directly studied in an animal model. Therefore, the acute and subchronic effects of BUP or selective DA and NE reuptake inhibitors on food intake, body weight, locomotor activity, and interscapular temperature were determined in mice. Generally, selective inhibition of DA reuptake (by GBR12783) increased activity while selective inhibition of NE reuptake (by nisoxetine, NIS) decreased activity and temperature. BUP increased activity and temperature but subchronic BUP did not significantly reduce body weight due to a compensatory increase in food intake. Subchronic DA + NE reuptake inhibitor coadministration mimicked the effect of BUP on activity and temperature, but caused weight loss because daily food intake was not increased. The results of this study suggest that the mild weight loss effect of BUP in humans may be due to increased locomotion or heat production. More importantly, inhibition of DA + NE reuptake (with GBR + NIS) increased energy expenditure without a compensatory increase in food intake, supporting a role for novel combination catecholamine reuptake inhibitors in pharmacotherapy for obesity.

Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat

“…This notion is supported by the observation that stimulation of monoaminergic neurotransmission also impacts the metabolic rate by increasing energy expenditure, either directly by increasing thermogenesis through activation of peripheral b 3 adrenoceptors in brown adipose tissue, or indirectly by increasing central DA receptor-dependent motor activity. These combined effects are reported for a number of MRIs, including the dual NE/5-HT and NE/DA reuptake inhibitors, sibutramine, and buproprion, respectively (Connoley et al, 1999;Liu et al, 2004;Golozoubova et al, 2006;Billes and Cowley, 2008). Although it should be noted that no tolerance to the appetite suppressing effect of tesofensine is observed in clinical settings (Astrup et al, 2008a), one possibility that warrants further investigation is whether sustained weight loss with tesofensine may involve increased energy expenditure.…”

Leptin Action in the Dorsomedial Hypothalamus Increases Sympathetic Tone to Brown Adipose Tissue in Spite of Systemic Leptin Resistance

“…We measured the temperature of iBAT as a marker of both sympathoexcitation and increased energy expenditure. We have used iBAT temperature as an index of sympathetic outflow and of thermogenesis previously in other studies (Xiao et al, 2007;Billes and Cowley, 2008). We found that DIO mice have chronically elevated temperature (⌬ 0.6°C), compared with C57BL/6J mice fed a regular diet (controls) over 24 h ( p Ͻ 0.001), during both the light period and the dark period.…”

“…iBAT temperature and locomotor activity (LA) were measured as described previously (Billes and Cowley, 2008). Under isoflurane anesthesia E-Mitters were implanted beneath the iBAT pad between the scapulae.…”

Interaction of nicotinic receptors with bupropion: Structural, functional, and pre-clinical perspectives

“…Emotional effects of BP have also been observed in social interactions in mice [15] . Moreover, BP induces locomotor stimulation, although this activity is mild [16][17][18] . BP has also been found to decrease not only nicotine but also the addictive and craving effects elicited by methamphetamine in humans [19] , and by cocaine in rodents [20] , as well as morphine-induced tolerance and dependence in rodents [21] .…”