Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes

Abstract

Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy. Here, we report that pharmacological activation of the cold receptor transient receptor potential cation channel subfamily M member 8 (TRPM8) with agonist icilin mimics the metabolic benefits of cold exposure. In diet-induced obese (DIO) mice, treatment with icilin enhances energy expenditure, and decreases body weight, without affecting food intake. To further potentiate the thermogenic action profile of icilin and add complementary anorexigenic mechanisms, we set out to identify pharmacological partners next to icilin. To that end, we specifically targeted nicotinic acetylcholine receptor (nAChR) subtype alpha3beta4 (α3β4), which we had recognized as a potential regulator of energy homeostasis and glucose metabolism. Combinatorial targeting of TRPM8 and nAChR α3β4 by icilin and dimethylphenylpiperazinium (DMPP) orchestrates synergistic anorexic and thermogenic pathways to reverse diet-induced obesity, dyslipidemia, and glucose intolerance in DIO mice.

Pharmacological targeting of α3β4 nicotinic receptors improves peripheral insulin sensitivity in mice with diet-induced obesity

“…Chronic DMPP improves glucose tolerance independent of changes in body weight, via CHRNB4, and without increasing insulin secretion Chronic treatment with DMPP improves glucose tolerance in DIO mice [2]. However, it is unknown whether this: (1) occurs independently of changes in body weight; (2) requires functional α3β4 nAChRs; and (3) is the consequence of increased insulin secretion or improved peripheral insulin sensitivity.…”

“…In skeletal muscle, canonical insulin signalling for glucose uptake was not altered by DMPP, while inhibitory glycogen synthase phosphorylation was decreased and muscle glycogen content increased. DMPP has previously been shown to lower body weight and improve glucose tolerance [2], yet it was unclear whether the glycaemic benefit is secondary to the decrease in body weight. By pair-feeding mice to DMPP-treated mice we show that DMPP lowers body weight primarily by inhibiting food intake, as the pair-fed vehicle-treated and DMPP-treated mice lost similar amounts of body weight.…”

“…In addition, we made the serendipitous observation that DMPP treatment for 7 days also robustly improved glucose tolerance. Even when administered at doses below the threshold needed to reduce body weight, DMPP ameliorated an impaired glucose tolerance [2]. This suggests that DMPP-mediated α3β4 nAChR engagement per se improves glucose tolerance; however, this has not been formally tested.…”

“…Obesity and associated metabolic disorders, such as type 2 diabetes, are major public health issues [1]. Considerable preclinical progress has been undertaken to tackle the obesity and type 2 diabetes pandemics, using different pharmacological strategies [2,3]. Recently, the activation of central nicotine receptors has been suggested as a promising target to reduce food intake [4].…”

“…We have recently shown that selective targeting of the α3β4 nAChRs with 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) reduces food intake and lowers body weight in diet-induced obese (DIO) mice [2]. In addition, we made the serendipitous observation that DMPP treatment for 7 days also robustly improved glucose tolerance.…”