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

Abstract

Aims/hypothesis Treatment with the α3β4 nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4phenylpiperazinium iodide (DMPP), improves glucose tolerance in diet-induced obese (DIO) mice, but the physiological and molecular mechanisms are unknown. Methods DMPP (10 mg/kg body weight, s.c.) was administered either in a single injection (acute) or daily for up to 14 days (chronic) in DIO wild-type (WT) and Chrnb4 knockout (KO) mice and glucose tolerance, tissue-specific tracer-based glucose metabolism, and insulin signalling were assessed. Results In WT mice, but not in Chrnb4 KO mice, single acute treatment with DMPP induced transient hyperglycaemia, which was accompanied by high plasma adrenaline (epinephrine) levels, upregulated hepatic gluconeogenic genes, and decreased hepatic glycogen content. In contrast to these acute effects, chronic DMPP treatment in WT mice elicited improvements in glucose tolerance already evident after three consecutive days of DMPP treatment. After seven days of DMPP treatment, glucose tolerance was markedly improved, also in comparison with mice that were pair-fed to DMPPtreated mice. The glycaemic benefit of chronic DMPP was absent in Chrnb4 KO mice. Chronic DMPP increased insulinstimulated glucose clearance into brown adipose tissue (+69%), heart (+93%), gastrocnemius muscle (+74%) and quadriceps muscle (+59%), with no effect in white adipose tissues. After chronic DMPP treatment, plasma adrenaline levels did not increase following an injection with DMPP. In glucose-stimulated skeletal muscle, we detected a decreased phosphorylation of the inhibitory Ser640 phosphorylation site on glycogen synthase and a congruent increase in glycogen accumulation following chronic DMPP treatment. Conclusions/interpretation Our data suggest that DMPP acutely induces adrenaline release and hepatic glycogenolysis, while chronic DMPP-mediated activation of β4-containing nAChRs improves peripheral insulin sensitivity independently of changes in body weight via mechanisms that could involve increased non-oxidative glucose disposal into skeletal muscle.

Divergent Roles of α5 and β4 Nicotinic Receptor Subunits in Food Reward and Nicotine-induced Weight Loss in Male Mice

“…Moreover, we demonstrate that nAChRs containing β4 subunits are indispensable for the effects of nicotine on food intake and weight loss and that they are important for the benefits of GLP-1R agonism on glucose metabolism. In agreement with previous work ( 50 ), these findings suggest that ligands selective for β4-nAChRs hold promise for targeting the inherent benefits of nicotinic receptor activity on energy metabolism.…”

“…Whereas the liraglutide-induced weight loss was intact in both α5 KO and β4 KO mice, the effect of liraglutide on reversing diet-induced glucose intolerance was impaired in β4 KO mice. The implication of β4-nAChRs in glucose metabolism is supported by previous work demonstrating that pharmacological activation of α3β4-nAChRs improves peripheral insulin sensitivity and reverses diet-induced glucose intolerance in mice ( 33 , 50 ). Together, these findings encourage further investigations into nAChRs, and in particular β4-nAChRs, in physiological and pharmacological regulation of glucose metabolism.…”

Rare Missense Variants of the Human β4 Subunit Alter Nicotinic α3β4 Receptor Plasma Membrane Localisation

“…Because of their roles both in the periphery and in the central nervous system, α3β4 nAChRs have attracted increasing interest as potential drug targets in therapeutic applications for nicotine addiction [ 8 , 9 , 10 ], respiratory diseases [ 16 ], diabetes [ 17 ] and cardiac hypertension [ 18 ]. Hence, in recent years, a number of groups, including ours, have addressed the pharmacology, as well as the cell biology, of these receptors.…”

Characterization of Binding Site Interactions and Selectivity Principles in the α3β4 Nicotinic Acetylcholine Receptor

“…Here, we focus on the nAChR subtype formed from the α3 and β4 subunits. This subtype is also known as the ganglionic nAChR because it partially mediates signal transmission from the central nervous system to the autonomic nervous system, which in turn controls involuntary functions of internal organs. , The α3β4 subtype is also expressed in several brain nuclei, where it participates in reward, aversion, dependence, and withdrawal of nicotine and other drugs and is thus a potential target for antiaddiction therapeutics. , In addition, findings linking α3β4 to conditions such respiratory diseases, diabetes, and cardiac hypertension have sparked recent interest in this subtype.…”

“…7,8 The α3β4 subtype is also expressed in several brain nuclei, where it participates in reward, aversion, dependence, and withdrawal of nicotine and other drugs and is thus a potential target for antiaddiction therapeutics. 9,10 In addition, findings linking α3β4 to conditions such respiratory diseases, 11 diabetes, 12 and cardiac hypertension 13 have sparked recent interest in this subtype.…”