Adipose Tissue Macrophage-Derived Exosomal miRNAs Can Modulate In Vivo and In Vitro Insulin Sensitivity

Abstract The Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) is a nuclear corepressor, regulating the transcriptional activity of many transcription factors critical for metabolic processes. While the importance of the role of SMRT in the adipocyte has been well-established, our comprehensive understanding of its in vivo function in the context of homeostatic maintenance is limited due to contradictory phenotypes yielded by prior generalized knockout mouse models. Multiple such models agree that SMRT deficiency leads to increased adiposity, although the effects of SMRT loss on glucose tolerance and insulin sensitivity have been variable. We therefore generated an adipocyte-specific SMRT knockout (adSMRT-/-) mouse to more clearly define the metabolic contributions of SMRT. In doing so, we found that SMRT deletion in the adipocyte does not cause obesity—even when mice are challenged with a high-fat diet. This suggests that adiposity phenotypes of previously described models were due to effects of SMRT loss beyond the adipocyte. However, an adipocyte-specific SMRT deficiency still led to dramatic effects on systemic glucose tolerance and adipocyte insulin sensitivity, impairing both. This metabolically deleterious outcome was coupled with a surprising immune phenotype, wherein most genes differentially expressed in the adipose tissue of adSMRT-/- mice were upregulated in pro-inflammatory pathways. Flow cytometry and conditioned media experiments demonstrated that secreted factors from knockout adipose tissue strongly informed resident macrophages to develop a pro-inflammatory, MMe (metabolically activated) phenotype. Together, these studies suggest a novel role for SMRT as an integrator of metabolic and inflammatory signals to maintain physiological homeostasis.

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HIV antiretroviral treatment alters adipokine expression and insulin sensitivity of adipose tissue in vitro and in vivo

Biochimie ◽

10.1016/j.biochi.2004.12.007 ◽

2005 ◽

Vol 87 (1) ◽

pp. 65-71 ◽

Cited By ~ 48

Author(s):

Claire Lagathu ◽

Minji Kim ◽

Mustapha Maachi ◽

Corinne Vigouroux ◽

Pascale Cervera ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Antiretroviral Treatment ◽

Adipose Tissue In Vitro

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Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00110.2003 ◽

2003 ◽

Vol 285 (3) ◽

pp. E527-E533 ◽

Cited By ~ 438

Author(s):

Jens M. Bruun ◽

Aina S. Lihn ◽

Camilla Verdich ◽

Steen B. Pedersen ◽

Søren Toubro ◽

...

Keyword(s):

Weight Loss ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Mrna Levels ◽

Plasma Adiponectin ◽

Tnf Α ◽

Adiponectin Mrna ◽

Before And After

Adiponectin is an adipose tissue-specific protein that is abundantly present in the circulation and suggested to be involved in insulin sensitivity and development of atherosclerosis. Because cytokines are suggested to regulate adiponectin, the aim of the present study was to investigate the interaction between adiponectin and three adipose tissue-derived cytokines (IL-6, IL-8, and TNF-α). The study was divided into three substudies as follows: 1) plasma adiponectin and mRNA levels in adipose tissue biopsies from obese subjects [mean body mass index (BMI): 39.7 kg/m2, n = 6] before and after weight loss; 2) plasma adiponectin in obese men (mean BMI: 38.7 kg/m2, n = 19) compared with lean men (mean BMI: 23.4 kg/m2, n = 10) before and after weight loss; and 3) in vitro direct effects of IL-6, IL-8, and TNF-α on adiponectin mRNA levels in adipose tissue cultures. The results were that 1) weight loss resulted in a 51% ( P < 0.05) increase in plasma adiponectin and a 45% ( P < 0.05) increase in adipose tissue mRNA levels; 2) plasma adiponectin was 53% ( P < 0.01) higher in lean compared with obese men, and plasma adiponectin was inversely correlated with adiposity, insulin sensitivity, and IL-6; and 3) TNF-α ( P < 0.01) and IL-6 plus its soluble receptor ( P < 0.05) decreased adiponectin mRNA levels in vitro. The inverse relationship between plasma adiponectin and cytokines in vivo and the cytokine-induced reduction in adiponectin mRNA in vitro suggests that endogenous cytokines may inhibit adiponectin. This could be of importance for the association between cytokines (e.g., IL-6) and insulin resistance and atherosclerosis.

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Telmisartan Improves Insulin Resistance and Modulates Adipose Tissue Macrophage Polarization in High-Fat-Fed Mice

Endocrinology ◽

10.1210/en.2010-1312 ◽

2011 ◽

Vol 152 (5) ◽

pp. 1789-1799 ◽

Cited By ~ 66

Author(s):

Shiho Fujisaka ◽

Isao Usui ◽

Yukiko Kanatani ◽

Masashi Ikutani ◽

Ichiro Takasaki ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Macrophage Polarization ◽

High Fat ◽

Adipose Tissues ◽

Tissue Macrophage ◽

Adipose Tissue Macrophage ◽

Visceral Adipose

Diet-induced obesity is reported to induce a phenotypic switch in adipose tissue macrophages from an antiinflammatory M2 state to a proinflammatory M1 state. Telmisartan, an angiotensin II type 1 receptor blocker and a peroxisome proliferator-activated receptor-γ agonist, reportedly has more beneficial effects on insulin sensitivity than other angiotensin II type 1 receptor blockers. In this study, we studied the effects of telmisartan on the adipose tissue macrophage phenotype in high-fat-fed mice. Telmisartan was administered for 5 wk to high-fat-fed C57BL/6 mice. Insulin sensitivity, macrophage infiltration, and the gene expressions of M1 and M2 markers in visceral adipose tissues were then examined. An insulin- or a glucose-tolerance test showed that telmisartan treatment improved insulin resistance, decreasing the body weight gain, visceral fat weight, and adipocyte size without affecting the amount of energy intake. Telmisartan reduced the mRNA expression of CD11c and TNF-α, M1 macrophage markers, and significantly increased the expressions of M2 markers, such as CD163, CD209, and macrophage galactose N-acetyl-galactosamine specific lectin (Mgl2), in a quantitative RT-PCR analysis. A flow cytometry analysis showed that telmisartan decreased the number of M1 macrophages in visceral adipose tissues. In conclusion, telmisartan improves insulin sensitivity and modulates adipose tissue macrophage polarization to an antiinflammatory M2 state in high-fat-fed mice.

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PPAR delta regulates adipose tissue macrophage activation and insulin sensitivity. Critical roles of PPAR delta in macrophage‐adipocyte crosstalk and insulin sensitivity

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.1018.1 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Kihwa Kang ◽

Volkan Karabacak ◽

Shannon M Reilly ◽

Kelly Fitzgerald ◽

Ben Hatano ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Macrophage Activation ◽

Tissue Macrophage ◽

Adipose Tissue Macrophage ◽

Ppar Delta

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PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814522115 ◽

2018 ◽

Vol 115 (48) ◽

pp. 12102-12111 ◽

Cited By ~ 6

Author(s):

Takeshi Katafuchi ◽

William L. Holland ◽

Rahul K. Kollipara ◽

Ralf Kittler ◽

David J. Mangelsdorf ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Mutant Mice ◽

Covalent Attachment ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation and is the target for the insulin-sensitizing thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In cell-based in vitro studies, the transcriptional activity of PPARγ is inhibited by covalent attachment of small ubiquitin-related modifier (SUMOylation) at K107 in its N terminus. However, whether this posttranslational modification is relevant in vivo remains unclear. Here, using mice homozygous for a mutation (K107R) that prevents SUMOylation at this position, we demonstrate that PPARγ is SUMOylated at K107 in white adipose tissue. We further show that in the context of diet-induced obesity PPARγ-K107R–mutant mice have enhanced insulin sensitivity without the corresponding increase in adiposity that typically accompanies PPARγ activation by TZDs. Accordingly, the PPARγ-K107R mutation was weaker than TZD treatment in stimulating adipocyte differentiation in vitro. Moreover, we found that both the basal and TZD-dependent transcriptomes of inguinal and epididymal white adipose tissue depots were markedly altered in the K107R-mutant mice. We conclude that PPARγ SUMOylation at K107 is physiologically relevant and may serve as a pharmacologic target for uncoupling PPARγ’s beneficial insulin-sensitizing effect from its adverse effect of weight gain.

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Reduced Adipose Tissue Macrophage Content Is Associated With Improved Insulin Sensitivity in Thiazolidinedione-Treated Diabetic Humans

Diabetes ◽

10.2337/db12-0868 ◽

2013 ◽

Vol 62 (6) ◽

pp. 1843-1854 ◽

Cited By ~ 51

Author(s):

S. Koppaka ◽

S. Kehlenbrink ◽

M. Carey ◽

W. Li ◽

E. Sanchez ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Tissue Macrophage ◽

Adipose Tissue Macrophage

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The role of GM-CSF in adipose tissue inflammation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00061.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. E1038-E1046 ◽

Cited By ~ 60

Author(s):

Dong-Hoon Kim ◽

Darleen Sandoval ◽

Jacquelyn A. Reed ◽

Emily K. Matter ◽

Emeline G. Tolod ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Knockout Mice ◽

Wild Type ◽

Tissue Macrophage ◽

Gm Csf ◽

Adipose Tissue Macrophage ◽

Mesenteric Fat

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine that has a central action to reduce food intake and body weight. Consistent with this, GM-CSF knockout mice are more obese and hyperphagic than wild-type mice. However, in lung, GM-CSF is an important determinant of macrophage infiltration. Consequently, we sought to determine if GM-CSF might contribute to adipose tissue macrophage accumulation, insulin resistance, and low-grade inflammation that occurs when animals gain weight on a high-fat diet (HFD). We therefore determined how targeted genetic disruption of GM-CSF can affect adipose tissue macrophage and cytokine gene expression as well as glucose homeostasis by performing hyperinsulinemic-euglycemic clamps. The number of macrophages and CCR2 gene expression in adipose tissue of GM-CSF knockout mice was decreased relative to those in wild-type mice, and the adipocyte size of mesenteric fat was increased in GM-CSF knockout mice on a HFD compared with wild-type mice. The level of mRNA of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α, and macrophage inflammatory protein-1α was significantly lower in mesenteric fat of GM-CSF knockout mice on the HFD than in wild-type mice. Using the hyperinsulinemic-euglycemic clamp technique, GM-CSF knockout mice had greater overall insulin sensitivity. This increase was due to enhanced peripheral uptake and utilization of glucose rather than to increased hepatic insulin sensitivity. Collectively, the data suggest that the GM-CSF knockout mutation ameliorates peripheral insulin resistance in spite of increased adiposity by reducing inflammation in adipose tissue in response to a HFD.

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