Nicotinic Acetylcholine Receptor Signaling in the Hypothalamus: Mechanisms Related to Nicotine's Effects on Food Intake

Abstract

Despite health risks associated with smoking, up to 20% of the US population persist in this behavior; many smoke to control body weight or appetite, and fear of post-cessation weight gain can motivate continued smoking. Nicotine and tobacco use is associated with lower body weight, and cessation yields an average weight gain of about 4 kg, which is thought to reflect a return to the body weight of a typical nonsmoker. Nicotine replacement therapies can delay this weight gain but do not prevent it altogether, and the underlying mechanism for how nicotine is able to reduce weight is not fully understood. In rodent models, nicotine reduces weight gain, reduces food consumption, and alters energy expenditure, but these effects vary with duration and route of nicotine administration. Nicotine, acting through nicotinic acetylcholine receptors (nAChRs), increases the firing rate of both orexigenic agouti-related peptide and anorexigenic proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus (ARC). Manipulation of nAChR subunit expression within the ARC can block the ability of nicotine and the nicotinic agonist cytisine from decreasing food intake; however, it is unknown exactly how this reduces food intake. This review summarizes the clinical and preclinical work on nicotine, food intake, and weight gain, then explores the feeding circuitry of the ARC and how it is regulated by nicotine. Finally, we propose a novel hypothesis for how nicotine acts on this hypothalamic circuit to reduce food intake. Implications: This review provides a comprehensive and updated summary of the clinical and preclinical work examining nicotine and food intake, as well as a summary of recent work examining feeding circuits of the hypothalamus. Synthesis of these two topics has led to new understanding of how nAChR signaling regulates food intake circuits in the hypothalamus.

Figure 1.

Feeding circuits in the arcuate nucleus of the hypothalamus (ARC). (A) Sagittal and coronal representations of the anatomical location of the ARC in the mouse brain. (B) agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neurons found in the ARC project to similar downstream target regions. AgRP neurons form inhibitory synapses on POMC neurons, but this connection is not reciprocal. (C) A fed or sated state corresponds with increased activity of POMC neurons, whereas the fasted state is associated with higher activity in AgRP cells. The balance of activity in these two neuronal populations regulates the relationship between food intake and energy expenditure. Adapted from Dietrich and Horvath.

Figure 2.

Localization and composition of nicotinic acetylcholine receptor (nAChR) subtypes. (A) Illustration of pentameric, transmembrane nAChRs and their localization in the neuron including somatic, pre-synaptic, post-synaptic, or peri-synaptic sites. nAChRs are produced and assembled in the endoplasmic reticulum, also depicted. (B) Illustration of receptor subunit arrangement and localization of the acetylcholine (ACh) binding sites in heteromeric or homomeric nAChR subtypes, with common subunit partners from the central nervous system shown. Modified from Gotti et al. and Zoli et al.

Figure 3.

Hypothesized model of nicotine’s effcts on the arcuate nucleus of the hypothalamus (ARC) feeding circuit. (A) After a 24-h fast, agouti-related peptide (AgRP) neurons (left) have an increased firing rate and proopiomelanocortin (POMC) neurons (right) have a reduced firing rate. (B) On the presentation of food, AgRP neuron firing rapidly decreases, while POMC neuron activity increases. In the presence of nicotine, AgRP neurons do not reduce their firing rate to the same degree because of activation by nicotine. POMC neurons are also hyper-excited. (C) This yields a net reduction in food intake because of the failed coding of caloric availability signaled by AgRP neurons. Neuronal traces in panel B are hypothesized responses to acute nicotine while in a fasted state.