Access to nicotine in drinking water reduces weight gain without changing caloric intake on high fat diet in male C57BL/6J mice

- Nicotine in drinking water decreases weight gain on HFD, but not chow, in male mice.
- Self-titrated nicotine does not change calorie intake in male or female mice.
- Nicotine and HFD change the expression of feeding peptides in the arcuate nucleus.

Nicotine and tobacco use is associated with lower body weight, and many smokers report concerns about weight. In animal studies, nicotine reduces weight gain, reduces food consumption, and alters energy expenditure, but these effects vary with duration and route of nicotine administration. Previous studies have used standardized nicotine doses, however, in this study, male and female mice had free access to nicotine drinking water for 30 days while fed either a high fat diet (HFD) or chow, allowing animals to titrate their nicotine intake. In male mice, HFD increased body weight and caloric intake. Nicotine attenuated this effect and decreased weight gain per calorie consumed without affecting overall caloric intake or acute locomotion, suggesting metabolic changes. Nicotine did not decrease weight in chow-fed animals. In contrast, the same paradigm did not result in significant differences in weight gain in female animals, but did alter corticosterone levels and locomotion, indicating sex differences in the response to HFD and nicotine. We measured levels of mRNAs encoding nicotinic acetylcholine receptor subunits, uncoupling proteins (UCP) 1-3, and neuropeptides involved in energy balance in adipose tissues and the arcuate nucleus of the hypothalamus (ARC). HFD and nicotine regulated UCP levels in adipose tissues and ARC from female, but not male, mice. Regulation of agouti-related peptide, neuropeptide-Y, melanin-concentrating hormone, and cocaine- and amphetamine-regulated transcript in ARC varied with diet and nicotine in a sex-dependent manner. These data demonstrate that chronic consumption of nicotine moderates the effect of HFD in male mice by changing metabolism rather than food intake, and identify a differential effect on female mice.