The key role of a glucagon-like peptide-1 receptor agonist in body fat redistribution

in Journal of Endocrinology
Correspondence should be addressed to N Wang or M D Jensen or Y Lu: wnj486@126.com or jensen@mayo.edu or luyingli2008@126.com

*(L Zhao, C Zhu and M Lu contributed equally to this work)

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Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an ideal therapy for type 2 diabetes and, as of recently, for obesity. In contrast to visceral fat, subcutaneous fat appears to be protective against metabolic diseases. Here, we aimed to explore whether liraglutide, a GLP-1RA, could redistribute body fat via regulating lipid metabolism in different fat depots. After being fed a high-fat diet for 8 weeks, 50 male Wistar and Goto-Kakizaki rats were randomly divided into a normal control group, a diabetic control group, low- and high-dose liraglutide-treated groups and a diet-control group. Different doses of liraglutide (400 μg/kg/day or 1200 μg/kg/day) or an equal volume of normal saline were administered to the rats subcutaneously once a day for 12 weeks. Body composition and body fat deposition were measured by dual-energy X-ray absorptiometry and MRI. Isotope tracers were infused to explore lipid metabolism in different fat depots. Quantitative real-time PCR and Western blot analyses were conducted to evaluate the expression of adipose-related genes. The results showed that liraglutide decreased visceral fat and relatively increased subcutaneous fat. Lipogenesis was reduced in visceral white adipose tissue (WAT) but was elevated in subcutaneous WAT. Lipolysis was also attenuated, and fatty acid oxidation was enhanced. The mRNA expression levels of adipose-related genes in different tissues displayed similar trends after liraglutide treatment. In addition, the expression of browning-related genes was upregulated in subcutaneous WAT. Taken together, the results suggested that liraglutide potentially redistributes body fat and promotes browning remodeling in subcutaneous WAT to improve metabolic disorders.

 

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    The platform and protocol for isotope tracer infusion in rats. (A) Experimental setup for tracer infusion. The lateral tail vein was catheterized for tracer infusion, and the tail artery for blood collection. To minimize the experimental stress, all rats were conscious and relaxed, with the ability to groom themselves as normal and drink water freely throughout the experiments. (B) This figure shows the process of tracer infusion and blood collection.

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    Liraglutide attenuated glucose levels, food intake, body weight gain and insulin resistance. (A) Dose-dependent improvement of fasting blood glucose (FBG) levels. (B) Dose-independent improvement of postprandial blood glucose (PBG) levels. (C) Dose-independent inhibition of food intake. (D) Dose-independent attenuation of body weight gain. (E) Decreases in fasting insulin (FINS) levels. (F) Improvement of insulin resistance. (G) Elevation of insulin sensitivity. The above indicators were assayed in all rats (n = 10 in each group). Data are presented as the mean ± s.e.m. *P < 0.05, vs Wistar + NS group; #P < 0.05, vs GK + NS group; &P < 0.05, vs GK + LIRA (400 µg/kg/day) group; φP < 0.05, vs GK + LIRA (1200 µg/kg/day) group.

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    Liraglutide improved lipid profiles and leptin and adiponectin levels. (A) Triglyceride (TG) levels. (B) Total cholesterol (TC) levels. (C) Low-density lipoprotein-cholesterol (LDL) levels. (D) Non-esterified fatty acid (NEFA) levels. (E) Leptin levels. (F) Adiponectin levels. The above indicators were assayed in all rats (n = 10 in each group). Data are presented as the mean ± s.e.m. *P < 0.05, vs Wistar + NS group; #P < 0.05, vs GK + NS group; &P < 0.05, vs GK + LIRA (400 µg/kg/day) group; φP < 0.05, vs GK + LIRA (1200 µg/kg/day) group.

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    Liraglutide reduced whole-body fat mass, especially visceral fat mass. (A and B) Reduction in whole-body fat mass. Dual-energy X-ray imaging showed that liraglutide significantly reduced the body fat ratios in a dose-independent manner. (C and D) Images of visceral and subcutaneous fat deposition with magnetic resonance imaging (MRI). Liraglutide considerably decreased visceral fat accumulation, while subcutaneous fat accumulation appeared to be slightly increased in a dose-dependent manner. The above indicators were assayed in all rats (n = 10 in each group). *P < 0.05, vs Wistar + NS group; #P < 0.05, vs GK + NS group.

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    Liraglutide improved hepatic steatosis and reduced adipocyte size in different fat depots. (A) HE staining of liver tissues (magnification ×200). (B) Oil red O staining of liver tissues (magnification ×200). (C) Area ratios of oil red O staining. Liraglutide or food restriction dramatically decreased ectopic lipid accumulation in the liver after intervention for 12 weeks. (D) HE staining of mesenteric white adipose tissue (WAT) (magnification ×200). (E) HE staining of inguinal WAT (magnification ×200). (F) HE staining of cluneal WAT (magnification ×200). Liver or adipose tissues in different fat depots were all randomly chosen from the five groups (n = 5 in each group). *P < 0.05, vs Wistar + NS group; #P < 0.05, vs GK + NS group; &P < 0.05, vs GK + LIRA (400 µg/kg/day) group; φP < 0.05, vs GK + LIRA (1200 µg/kg/day) group.

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    Liraglutide redistributed visceral and subcutaneous fat deposition by regulating lipid metabolism in different tissues. (A) Deposition rates of TG in different tissues. (B) Ratio of lipid deposition in the subcutaneous white adipose tissue (WAT) to that in the visceral WAT. (C) Triglyceride (TG) synthetic rates in different tissues. (D) Inhibition of lipolysis. (E) Enhancement of fatty acid β-oxidation in skeletal muscle. The above indicators were assayed in all rats (n = 10 in each group). Data are presented as the mean ± s.e.m. *P < 0.05, vs Wistar + NS group; #P < 0.05, vs GK + NS group; &P < 0.05, vs GK + LIRA (400 µg/kg/day) group; φP < 0.05, vs GK + LIRA (1200 µg/kg/day) group.

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    Liraglutide regulated the mRNA expression levels of genes related to lipid metabolism in different tissues. (A and B) mRNA expression levels of key enzymes (Mgat, Dgat2) involved in triglyceride (TG) synthesis. (C) mRNA expression levels of a key enzyme (Hsl) involved in TG degradation. (D and E) mRNA expression levels of key enzymes (Cpt1a, Cpt1b) for fatty acid β-oxidation. (F) mRNA expression levels of Ucp1 in different fat depots. (G) mRNA expression levels of Pgc1α in different fat depots. (H) mRNA expression levels of Bmp4 in different fat depots. Liver, skeletal muscle or adipose tissues in different fat depots were all randomly chosen from the five groups (n = 5 in each group). Data are expressed as the mean ± s.e.m. *P < 0.05, vs Wistar + NS group; #P < 0.05, vs GK + NS group; &P < 0.05, vs GK + LIRA (400 µg/kg/day) group; φP < 0.05, vs GK + LIRA (1200 µg/kg/day) group.

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    Liraglutide upregulated UCP1 protein expression in the subcutaneous fat depots. There was no significant difference in the UCP1 protein expression levels between the four groups in the brown adipose tissue (BAT) (A) and visceral (mesenteric) white adipose tissue (WAT) (B); however, the UCP1 levels were significantly upregulated in the subcutaneous (inguinal and cluneal) WAT (C and D) after liraglutide intervention. Adipose tissues in different fat depots were all randomly chosen from the five groups (n = 4 in each group). *P < 0.05, vs Wistar + NS group; #P < 0.05, vs GK + NS group; &P < 0.05, vs GK + LIRA (400 µg/kg/day) group; φP < 0.05, vs GK + LIRA (1200 µg/kg/day) group.

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