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CD47 deficiency protects mice from diet-induced obesity and improves whole body glucose tolerance and insulin sensitivity.

Maimaitiyiming H, Norman H, Zhou Q, Wang S - Sci Rep (2015)

Bottom Line: CD47 is a transmembrane protein with several functions including self-recognition, immune cell communication, and cell signaling.This led to decreased MCP1/CCR2 dependent macrophage infiltration into adipose tissue and reduced inflammation, resulting in improved glucose tolerance and insulin sensitivity.In addition, CD47 deficiency stimulated the expression of UCP1 and carnitine palmitoyltransferase 1b (CPT1b) levels in brown adipose tissue, leading to increased lipid utilization and heat production.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536; Lexington Veterans Affairs Medical Center, Lexington, KY.

ABSTRACT
CD47 is a transmembrane protein with several functions including self-recognition, immune cell communication, and cell signaling. Although it has been extensively studied in cancer and ischemia, CD47 function in obesity has never been explored. In this study, we utilized CD47 deficient mice in a high-fat diet induced obesity model to study for the first time whether CD47 plays a role in the development of obesity and metabolic complications. Male CD47 deficient and wild type (WT) control mice were fed with either low fat (LF) or high fat (HF) diets for 16 weeks. Interestingly, we found that CD47 deficient mice were protected from HF diet-induced obesity displaying decreased weight gain and reduced adiposity. This led to decreased MCP1/CCR2 dependent macrophage infiltration into adipose tissue and reduced inflammation, resulting in improved glucose tolerance and insulin sensitivity. In addition, CD47 deficiency stimulated the expression of UCP1 and carnitine palmitoyltransferase 1b (CPT1b) levels in brown adipose tissue, leading to increased lipid utilization and heat production. This contributes to the increased energy utilization and reduced adiposity observed in these mice. Taken together, these data revealed a novel role for CD47 in the development of obesity and its related metabolic complications.

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Related in: MedlinePlus

HF-fed CD47 deficient mice displayed reduced systemic inflammation compared to HF-fed wild type controls.Plasma TNF-α (A), IL-6 (B), and IL-10 (C) levels were measured by ELISA as described in Methods. Data are presented as mean ± SE (n = 7 mice/group), *P < 0.05 and ** P < 0.01.
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f2: HF-fed CD47 deficient mice displayed reduced systemic inflammation compared to HF-fed wild type controls.Plasma TNF-α (A), IL-6 (B), and IL-10 (C) levels were measured by ELISA as described in Methods. Data are presented as mean ± SE (n = 7 mice/group), *P < 0.05 and ** P < 0.01.

Mentions: Systemic as well as adipose tissue inflammation were determined in four groups of mice. As shown in Fig. 2A,B, HF-fed CD47 deficient mice had significant reduction in plasma TNF-α and IL-6 levels. In addition to the reduced plasma pro-inflammatory cytokines, plasma anti-inflammatory cytokine-IL-10 levels were significantly increased in HF-fed CD47 deficient mice as compared to HF-fed WT mice or to LF-fed CD47 deficient mice (Fig. 2C), suggesting that the interaction between diet composition and genotype contributes to the IL-10 secretion. In addition to systemic inflammation, adipose tissue inflammation status was determined. Visceral adipose tissue has been suggested to be the primary source of cytokine and adipokine release within obesity-associated inflammation28. Moreover, increased accumulation of adipose tissue macrophages is a significant contributor to obesity- induced chronic inflammation293031. Therefore macrophage infiltration into adipose tissue was determined by immunohistochemical staining for macrophage marker-F4/80. As shown in Fig. 3A, HF-fed WT controls had robust positive staining of F4/80 and crown-like structures, yet HF-fed CD47 deficient mice had minimal positive staining, suggesting a decreased presence of macrophages. We confirmed this staining result with qPCR and demonstrated that HF-fed WT controls had a significant increase in F4/80 expression in adipose tissue, which was reduced in HF-fed CD47 deficient mice (Fig. 3B). Moreover, CD11c and TNF-α levels were increased in adipose tissue from HF-fed WT mice, but decreased in HF-fed CD47deficient mice (Fig. 3B). Together, these data indicate that HF-fed CD47 deficient mice had reduced macrophage infiltration into adipose tissue and decreased systemic and adipose tissue inflammation.


CD47 deficiency protects mice from diet-induced obesity and improves whole body glucose tolerance and insulin sensitivity.

Maimaitiyiming H, Norman H, Zhou Q, Wang S - Sci Rep (2015)

HF-fed CD47 deficient mice displayed reduced systemic inflammation compared to HF-fed wild type controls.Plasma TNF-α (A), IL-6 (B), and IL-10 (C) levels were measured by ELISA as described in Methods. Data are presented as mean ± SE (n = 7 mice/group), *P < 0.05 and ** P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352923&req=5

f2: HF-fed CD47 deficient mice displayed reduced systemic inflammation compared to HF-fed wild type controls.Plasma TNF-α (A), IL-6 (B), and IL-10 (C) levels were measured by ELISA as described in Methods. Data are presented as mean ± SE (n = 7 mice/group), *P < 0.05 and ** P < 0.01.
Mentions: Systemic as well as adipose tissue inflammation were determined in four groups of mice. As shown in Fig. 2A,B, HF-fed CD47 deficient mice had significant reduction in plasma TNF-α and IL-6 levels. In addition to the reduced plasma pro-inflammatory cytokines, plasma anti-inflammatory cytokine-IL-10 levels were significantly increased in HF-fed CD47 deficient mice as compared to HF-fed WT mice or to LF-fed CD47 deficient mice (Fig. 2C), suggesting that the interaction between diet composition and genotype contributes to the IL-10 secretion. In addition to systemic inflammation, adipose tissue inflammation status was determined. Visceral adipose tissue has been suggested to be the primary source of cytokine and adipokine release within obesity-associated inflammation28. Moreover, increased accumulation of adipose tissue macrophages is a significant contributor to obesity- induced chronic inflammation293031. Therefore macrophage infiltration into adipose tissue was determined by immunohistochemical staining for macrophage marker-F4/80. As shown in Fig. 3A, HF-fed WT controls had robust positive staining of F4/80 and crown-like structures, yet HF-fed CD47 deficient mice had minimal positive staining, suggesting a decreased presence of macrophages. We confirmed this staining result with qPCR and demonstrated that HF-fed WT controls had a significant increase in F4/80 expression in adipose tissue, which was reduced in HF-fed CD47 deficient mice (Fig. 3B). Moreover, CD11c and TNF-α levels were increased in adipose tissue from HF-fed WT mice, but decreased in HF-fed CD47deficient mice (Fig. 3B). Together, these data indicate that HF-fed CD47 deficient mice had reduced macrophage infiltration into adipose tissue and decreased systemic and adipose tissue inflammation.

Bottom Line: CD47 is a transmembrane protein with several functions including self-recognition, immune cell communication, and cell signaling.This led to decreased MCP1/CCR2 dependent macrophage infiltration into adipose tissue and reduced inflammation, resulting in improved glucose tolerance and insulin sensitivity.In addition, CD47 deficiency stimulated the expression of UCP1 and carnitine palmitoyltransferase 1b (CPT1b) levels in brown adipose tissue, leading to increased lipid utilization and heat production.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536; Lexington Veterans Affairs Medical Center, Lexington, KY.

ABSTRACT
CD47 is a transmembrane protein with several functions including self-recognition, immune cell communication, and cell signaling. Although it has been extensively studied in cancer and ischemia, CD47 function in obesity has never been explored. In this study, we utilized CD47 deficient mice in a high-fat diet induced obesity model to study for the first time whether CD47 plays a role in the development of obesity and metabolic complications. Male CD47 deficient and wild type (WT) control mice were fed with either low fat (LF) or high fat (HF) diets for 16 weeks. Interestingly, we found that CD47 deficient mice were protected from HF diet-induced obesity displaying decreased weight gain and reduced adiposity. This led to decreased MCP1/CCR2 dependent macrophage infiltration into adipose tissue and reduced inflammation, resulting in improved glucose tolerance and insulin sensitivity. In addition, CD47 deficiency stimulated the expression of UCP1 and carnitine palmitoyltransferase 1b (CPT1b) levels in brown adipose tissue, leading to increased lipid utilization and heat production. This contributes to the increased energy utilization and reduced adiposity observed in these mice. Taken together, these data revealed a novel role for CD47 in the development of obesity and its related metabolic complications.

Show MeSH
Related in: MedlinePlus