An α7 Nicotinic Acetylcholine Receptor-Selective Agonist Reduces Weight Gain and Metabolic Changes in a Mouse Model of Diabetes

Abstract

Type 2 diabetes has become a pervasive public health problem. The etiology of the disease has not been fully defined but appears to involve abnormalities in peripheral and central nervous system pathways, as well as prominent inflammatory components. Because nicotinic acetylcholine receptors (nAChRs) are known to interact with anti-inflammatory pathways and have been implicated in control of appetite and body weight, as well as lipid and energy metabolism, we examined their role in modulating biological parameters associated with the disease. In a model of type 2 diabetes, the homozygous leptin-resistant db/db obese mouse, we measured the effects of a novel ␣7 nAChR-selective agonist [5-methyl-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide (TC-7020)] on body mass, glucose and lipid metabolism, and proinflammatory cytokines. Oral administration of TC-7020 reduced weight gain and food intake, reduced elevated glucose and glycated hemoglobin levels, and lowered elevated plasma levels of triglycerides and the proinflammatory cytokine tumor necrosis factor-␣. These changes were reversed by the ␣7-selective antagonist methyllycaconitine, confirming the involvement of ␣7 nAChRs. Prevention of weight gain, decreased food intake, and normalization of glucose levels were also blocked by the Janus kinase 2 (JAK2) inhibitor ␣-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG-490), suggesting that these effects involve linkage of ␣7 nAChRs to the JAK2-signal transducer and activator of transcription 3 signaling pathway. The results show that ␣7 nAChRs play a central role in regulating biological parameters associated with diabetes and support the potential of targeting these receptors as a new therapeutic strategy for treatment.In 2000 it was reported that at least 171 million people worldwide (2.8% of the population) suffered from diabetes, and it has been estimated that the incidence will almost double by the year 2030 (Wild et al., 2004). The Centers for Disease Control and Prevention has designated the disease an epidemic. Specific pathogenic entities contributing to diabetic risk, such as central adiposity, ectopic fat accumulation, hyperlipidemia, and inflammation, have been well characterized. In general, diabetes is believed to be secondary to an insulin-resistant state, which is associated with excess adiposity (Sykiotis and Papavassiliou, 2001). Insulin resistance in skeletal muscle, liver, and adipose tissue impedes glucose uptake and results in the release of free fatty acids and the characteristically associated dyslipidemia. Elevations in postprandial blood glucose levels and ultimately in fasting glucose levels result in compensatory hyperinsulinemia, a condition that is initially accompanied by islet ␤-cell hypertrophy and eventual failure (Sykiotis and Papavassiliou, 2001).A key factor that underlies the development of diabetes is a characteristic systemic inflammation, marked by increases in the venous blood concentrations of C-reactive protein, interleukin 6 (IL-6), and tum...

The nicotinic acetylcholine receptor α7 in subcutaneous mature adipocytes: downregulation in human obesity and modulation by diet-induced weight loss

“…23 It is also known that long-term stimulation of nAChRs contributes to ameliorate insulin sensitivity and that selective a7nAChR agonists are able to reduce weight gain, food intake and plasma levels of inflammatory cytokines in rat adipocytes and in a mouse genetic model of obesity. 23,14 These effects were completely abolished in a7nAChR KO mice treated with nicotine. 24 Although it is classically established that in humans obesity complications are principally attributable to increased visceral adipose mass and its secretion products, the results presented herein indicate that SAT might contribute to maintain the chronic low-grade inflammation, particularly in extreme obesity.…”

“…10,14 The a7nAChR can be considered to be a peripheral 'immune' component of the cholinergic anti-inflammatory pathway. 18,19 Molecular mechanisms supporting these anti-inflammatory effects include nuclear factor kappa B pathway inhibition, 20 activation of Janus activated kinase --signal transducer and activator of transcription 21 and the consequent inhibition of TNFa production.…”

“…12 The a7-subtype acetylcholine cholinergic receptor (a7nAChR) is involved in cognitive processes 10,13 and is present in circulating macrophages and immune cells, where it regulates the release of inflammatory cytokines such as tumor necrosis factor alpha (TNFa), interleukin-1 (IL1) and IL18. 10 In rat adipocytes, longterm stimulation of a7nAChR has been shown to improve insulin sensitivity by modulating adipokine secretion, 14 and in a mouse model of diabetes, a specific a7nAChR agonist was shown to reduce body weight and improve metabolic parameters. 14 These findings led to consider a7nAChR as a potential therapeutic target for treating the inflammatory components of obesity.…”

“…10 In rat adipocytes, longterm stimulation of a7nAChR has been shown to improve insulin sensitivity by modulating adipokine secretion, 14 and in a mouse model of diabetes, a specific a7nAChR agonist was shown to reduce body weight and improve metabolic parameters. 14 These findings led to consider a7nAChR as a potential therapeutic target for treating the inflammatory components of obesity. 8 In humans, expression of a7nAChR in non-neural cells has been demonstrated in cultured bronchial epithelial cells 15 and aortic endothelial cells, 16 but the role of the 'cholinergic anti-inflammatory pathway' in adipose tissue has been poorly investigated.…”

Nicotinic Cholinergic Signaling in Adipose Tissue and Pancreatic Islets Biology: Revisited Function and Therapeutic Perspectives

“…a7 nAChR deficiency seems to elevate adipose tissue infiltration by classically activated macrophages and leads to an inflammatory-prone status which induces insulin resistance. In contrast, pharmacological administration of the a7 nAChR agonist TC-7020 to db/db obese mice reduces their elevated glucose levels and lowers their elevated plasma levels of triglycerides and TNF-a (Marrero et al 2010). These benefits are abolished by both the a7-selective antagonist methyllycaconitine and a Janus kinase 2 inhibitor, confirming the involvement of a7 nAChRs and the downstream JAK2/ STAT3 signaling pathway (Marrero et al 2010).…”