Activation of the cholinergic antiinflammatory pathway ameliorates obesity-induced inflammation and insulin resistance.
Obesity is associated with a chronic inflammatory state characterized by adipose tissue macrophage infiltration and inflammation, which contributes to insulin resistance. The cholinergic antiinflammatory pathway, which acts through the macrophage α7-nicotinic acetylcholine receptor (α7nAChR), is important in innate immunity. Here we show that adipose tissue possesses a functional cholinergic signaling pathway. Activating this pathway by nicotine in genetically obese (db/db) and diet-induced obese mice significantly improves glucose homeostasis and insulin sensitivity without changes of body weight. This is associated with suppressed adipose tissue inflammation. In addition, macrophages from α7nAChR-/- [α7 knockout (α7KO)] mice have elevated proinflammatory cytokine production in response to free fatty acids and TNFα, known agents causing inflammation and insulin resistance. Nicotine significantly suppressed free fatty acid- and TNFα-induced cytokine production in wild type (WT), but not α7KO macrophages. These data suggest that α7nAChR is important in mediating the antiinflammatory effect of nicotine. Indeed, inactivating this pathway in α7KO mice results in significantly increased adipose tissue infiltration of classically activated M1 macrophages and inflammation in α7KO mice than their WT littermates. As a result, α7KO mice exhibit more severely impaired insulin sensitivity than WT mice without changes of body weight. These data suggest that the cholinergic antiinflammatory pathway plays an important role in obesity-induced inflammation and insulin resistance. Targeting this pathway may provide novel therapeutic benefits in the prevention and treatment of obesity-induced inflammation and insulin resistance.
Section on Gerontology and Geriatric Medicine, Department of Internal Medicine, Medical Center Boulevard, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA.
XianFeng
X
Wang
ZhengGang
Z
Yang
Bingzhong
B
Xue
Hang
H
Shi
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004032:Diet; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D007249:Inflammation / Q000209:etiology* / Q000503:physiopathology*; D007333:Insulin Resistance / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009538:Nicotine / Q000494:pharmacology; D009765:Obesity / Q000150:complications*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001786:Blood Glucose; C579166:Chrna7 protein, mouse; D016207:Cytokines; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D005947:Glucose
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