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, 145 (2), 366-74.e1-3

Association Between Specific Adipose Tissue CD4+ T-cell Populations and Insulin Resistance in Obese Individuals

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Association Between Specific Adipose Tissue CD4+ T-cell Populations and Insulin Resistance in Obese Individuals

Elisa Fabbrini et al. Gastroenterology.

Abstract

Background & aims: An increased number of macrophages in adipose tissue is associated with insulin resistance and metabolic dysfunction in obese people. However, little is known about other immune cells in adipose tissue from obese people, and whether they contribute to insulin resistance. We investigated the characteristics of T cells in adipose tissue from metabolically abnormal insulin-resistant obese (MAO) subjects, metabolically normal insulin-sensitive obese (MNO) subjects, and lean subjects. Insulin sensitivity was determined by using the hyperinsulinemic euglycemic clamp procedure.

Methods: We assessed plasma cytokine concentrations and subcutaneous adipose tissue CD4(+) T-cell populations in 9 lean, 12 MNO, and 13 MAO subjects. Skeletal muscle and liver samples were collected from 19 additional obese patients undergoing bariatric surgery to determine the presence of selected cytokine receptors.

Results: Adipose tissue from MAO subjects had 3- to 10-fold increases in numbers of CD4(+) T cells that produce interleukin (IL)-22 and IL-17 (a T-helper [Th] 17 and Th22 phenotype) compared with MNO and lean subjects. MAO subjects also had increased plasma concentrations of IL-22 and IL-6. Receptors for IL-17 and IL-22 were expressed in human liver and skeletal muscle samples. IL-17 and IL-22 inhibited uptake of glucose in skeletal muscle isolated from rats and reduced insulin sensitivity in cultured human hepatocytes.

Conclusions: Adipose tissue from MAO individuals contains increased numbers of Th17 and Th22 cells, which produce cytokines that cause metabolic dysfunction in liver and muscle in vitro. Additional studies are needed to determine whether these alterations in adipose tissue T cells contribute to the pathogenesis of insulin resistance in obese people.

Keywords: FFM; GIF; IFN; IL; JNK; Lymphocytes; MAO; MNO; Metabolically Abnormal Obesity; Metabolically Normal Obesity; NAFLD; c-Jun kinase; fat free mass; glucose infusion rate; interferon; interleukin; metabolically abnormal insulin-resistant obese; metabolically normal insulin-sensitive obese; nonalcoholic fatty liver disease.

Figures

Figure 1
Figure 1
Hepatic and skeletal muscle insulin sensitivity in study participants. Hepatic insulin sensitivity (A), assessed by using the Hepatic Insulin Sensitivity Index as a measure of endogenous glucose production in relation to plasma insulin concentration, and skeletal muscle insulin sensitivity (B), assessed as the stimulation of skeletal muscle glucose uptake during insulin infusion, are impaired in MAO subjects compared with MNO and lean subjects. One-way analysis of variance with planned contrasts was used to compare the differences between MAO and the other 2 groups. Values significantly different from the MAO group, *P < .001. Values are mean ± SEM.
Figure 2
Figure 2
Adipose tissue gene expression of CD4+ (A), CCL5 (B), and IL-7 (C) in lean, MNO, and MAO participants. Adipose tissue messenger RNA values increased progressively from lean to MNO to MAO subjects (*P value for linear trend <.05, by one-way analysis of variance on log-transformed data). Values are mean ± SEM.
Figure 3
Figure 3
Adipose tissue T-cell polarization and plasma IL-6 concentrations in lean, MNO, and MAO participants. MAO subjects show a distinctive polarization of CD 4+ T cells expanded from subcutaneous adipose tissue toward IL-22 (A) and IL-17 (B) producing cells. Plasma IL-6 concentration, known to stimulate lymphocyte polarization toward the Th17 and Th22 phenotype, is greater in MAO than both MNO and lean subjects (C). One-way analysis of variance with planned contrasts was used to compare the differences between MAO and the other 2 groups. Values significantly different from the MAO group; *P < .001, P < .05. Values are median and quartiles.
Figure 4
Figure 4
Effects of IL-17 and IL-22 on rat skeletal muscle 2-deoxyglucose (2-DG) uptake. Incubation of rat muscle strips with IL-17 or IL-22 inhibits insulin-stimulated increase in glucose uptake in soleus muscle (A), but not in epitroclearis muscle (B). Value for muscle incubated with IL-17 and IL-22 is significantly different than value for muscle incubated with vehicle; *P < .01. Values are mean ± SEM.
Figure 5
Figure 5
Effects of IL-17 and IL-22 on insulin-mediated glucose metabolism in primary human hepatocytes. Both IL-17 and IL-22 inhibit insulin-stimulated phosphorylation of Akt (A), insulin-mediated suppression of hepatocyte glucose production (release into the media) (B), and hepatocyte anerobic glucose metabolism (C). Western blotting analyses demonstrate that both IL-22 and IL-17 increase the phosphorylation of JNK (pJNK); total JNK (tJNK) is not affected by treatment with either cytokine (D). Pretreating human hepatocytes with a JNK inhibitor (PD098059) attenuated the increase in hepatocyte glucose production caused by IL-17 or IL-22 treatment in the presence of insulin and glucagon (E). Values for hepatocytes incubated with IL-17, IL-22 or JNK inhibitor are significantly different from vehicle values; *P < .01. Values are mean ± SEM.

Comment in

  • Obesity heats up adipose tissue lymphocytes.
    O'Rourke RW, Lumeng CN. O'Rourke RW, et al. Gastroenterology. 2013 Aug;145(2):282-5. doi: 10.1053/j.gastro.2013.06.026. Epub 2013 Jun 24. Gastroenterology. 2013. PMID: 23806542 Free PMC article. No abstract available.

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