Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Mar;152(3):836-46.
doi: 10.1210/en.2010-0855. Epub 2011 Jan 14.

Activation of the cholinergic antiinflammatory pathway ameliorates obesity-induced inflammation and insulin resistance

XianFeng Wang  1 , ZhengGang Yang, Bingzhong Xue, Hang Shi
Affiliations

Activation of the cholinergic antiinflammatory pathway ameliorates obesity-induced inflammation and insulin resistance

XianFeng Wang et al. Endocrinology. 2011 Mar.

Abstract

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.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Activation of the cholinergic antiinflammatory pathway by nicotine improves glucose homeostasis in db/db mice. db/db and lean control mice (8 wk of age) on chow diet were treated ip with 400 μg/kg nicotine twice daily for 3 wk. Fed (panel A) and fasting (panel B) glucose were measured after 3 wk of treatment (n = 5). Data are expressed as mean ± se. Statistical significance is indicated by the presence of different superscripts. Groups labeled with the same superscripts are not statistically different from each other. Groups labeled with different superscripts are statistically different from each other.
Fig. 2.
Fig. 2.
Activation of the cholinergic antiinflammatory pathway by nicotine improves insulin sensitivity in DIO mice. Male C57BL/6 mice (6 wk of age) were put on chow or HF diet for 11 wk followed by saline or nicotine (400 μg/kg) injection (ip) twice daily for 3 wk. Fed glucose (panel A) fed insulin (panel B) levels, GTT (panel C), and ITT (panel D) were assessed. GTT was performed in overnight fasted mice with ip injection of glucose at 1.2 g/kg of body weight. ITT was performed 4 h after food removal. Mice were ip injected with insulin at 1.5 U/kg (n = 10) for chow-saline for HF-saline (n = 5) and for HF-nicotine (n = 7) in panels A–D. E–G, Insulin signaling study was conducted at the end of 3-wk saline or nicotine treatment by ip injection of 10 U/kg insulin into overnight-fasted mice. Gastrocnemius muscle was collected 10 min later, and phosphorylation of IR at Tyr1162Tyr1163 (panel E), IRS1 Tyr612 (panel F), Akt/PKB at ser473 (panel G), and total IR, IRS1, and Akt/PKB were measured by Western blotting analysis. Bar graphs in panels E–G show phosphorylation levels of IR, IRS1, and Akt/PKB normalized to total IR, IRS1, and Akt/PKB levels (n = 5 each for chow-saline and HF-saline groups and n = 6 for HF-nicotine group). Data are expressed as mean ± se. In panels C and D: *, P < 0.05 vs. other two groups; in panels A, B, and E–G, statistical significance is indicated by the presence of different superscripts. Groups labeled with the same superscripts are not statistically different from each other. Groups labeled with different superscripts are statistically different from each other. Nic, Nicotine; Ins, insulin.
Fig. 3.
Fig. 3.
Activation of the cholinergic signaling pathway by nicotine suppresses adipose tissue inflammation in db/db mice. Serum TNFα (panel A), epididymal white adipose tissue (WAT) TNFα mRNA, and protein levels (panel B) were measured by ELISA. The expression of MCP1, F4/80, IL-6, IL-1β, and iNOS (panel C) was measured by real-time RT-PCR and normalized to cyclophilin (n = 5) in panels A–C. Data are expressed as mean ± se. Statistical significance is indicated by the presence of different superscripts. Groups labeled with the same superscripts are not statistically different from each other. Groups labeled with different superscripts are statistically different from each other. Nic, Nicotine.
Fig. 4.
Fig. 4.
α7nAChR mediates nicotine's antiinflammatory effect in peritoneal macrophages. TNFα (panel A), IL-1β (panel B), IL-6 expression (panel C), and TNFα secretion (panel D) in peritoneal macrophages treated with stearic acid (C18:0) in the presence or absence of nicotine. Peritoneal macrophages were isolated from WT or α7KO mice as described in Materials and Methods. Cells were pretreated with nicotine (1 μm) for 16–18 h and then treated with stearic acid (500 μm) in the presence or absence of nicotine for additional 4 h. The expression of target genes was measured by real-time RT-PCR and normalized to cyclophilin. TNFα secretion into the medium was measured by ELISA for treatments in WT groups (n = 3–4) and for treatments in KO groups (n = 5–6). Data are expressed as mean±se. Statistical significance is indicated by the presence of different superscripts. Groups labeled with the same superscripts are not statistically different from each other. Groups labeled with different superscripts are statistically different from each other. Nic, Nicotine.
Fig. 5.
Fig. 5.
α7KO mice have increased adipose tissue inflammation. A, Analysis of SVF cells for F4/80 and CD11c. Epididymal fat pads from male WT and α7KO mice on chow diet were separated into adipocyte and SVF populations. SVF cells were stained with antibodies against F4/80, CD11c, and isotype controls and analyzed by flow cytometry. Samples were gated for F4/80+ cells (upper panels) and examined for coexpression of CD11c (lower panels). Data from a representative experiment are shown. The percentage of CD11c+ cells within the F4/80+ ATM is indicated for each genotype. B and C, Quantitation of F4/80+CD11c+ ATM subpopulations in epididymal fat pads. Data were presented as total number of cells per mouse (panel B) and as cell numbers normalized to fat pad weight (panel C). In panels A–C, n = 8 for WT-LF and n = 6 for α7KO-LF. D–F, F4/80+CD11c+ cells in epididymal fat pads of WT and α7KO mice on HF diet. Data were presented as percentage of cells in SVF populations (panel D), number of cells per mouse (panel E), and number of cells per gram of fat pad (panel F). G, Gene expression profiles in epididymal fat pads from 6-month-old male WT and α7KO mice on HF diet. The expression of target genes was measured by real-time RT-PCR and normalized to cyclophilin (n = 4 in panels D–F and n = 3–4 in panel G). Data are expressed as mean ± se; *, P < 0.05.
Fig. 6.
Fig. 6.
α7KO mice develop insulin resistance on HF diet. A–C, Fed insulin levels (panel A), GTT (panel B), and ITT (panel C) in 6-month-old male WT and α7KO mice fed HF diet. GTT was performed in overnight fasted mice with ip injection of glucose at 1.5 g/kg of body weight. ITT was performed 4 h after food removal in mice with ip injection of insulin at 1.75 U/kg of body weight (n = 10 in panel A, n = 7 for WT, and n = 5 for α7KO in panel B and n = 4 in panel C. D–F, Glucose infusion rate (panel D), glucose turnover (panel E), and muscle glucose uptake (panel F) in 7- to 8-month-old male WT and α7KO mice on HF diet during hyperinsulinemic-euglycemic clamp study. Hyperinsulinemic-euglycemic clamp was performed as described in Materials and Methods (n = 6 in panels D–F). G and H, Insulin signaling study was conducted in 6-month-old male WT and α7KO mice on HF diet by ip injection of 10 U/kg insulin into overnight-fasted mice. Gastrocnemius muscle was collected 10 min later and phosphorylation of IR at Tyr1162Tyr1163 (panel G), IRS1 at Tyr612 (panel H), and total IR and IRS1 were measured by Western blotting analysis. Bar graphs show phosphorylation levels of IR and IRS1 normalized to total IR and IRS1 levels (n = 4). Data are expressed as mean ± se. *, P < 0.05 vs. WT mice.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Olefsky JM, Glass CK. 2010. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246 - PubMed
    1. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW., Jr 2003. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808 - PMC - PubMed
    1. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. 2003. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830 - PMC - PubMed
    1. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M. 2005. IKK-β links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198 - PubMed
    1. Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, Grivennikov S, Wynshaw-Boris A, Scadeng M, Olefsky JM, Karin M. 2007. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab 6:386–397 - PubMed

Publication types

MeSH terms