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Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.

ABSTRACT: Increased adipose tissue lipogenesis is associated with enhanced insulin sensitivity. Mice overexpressing the Glut4 glucose transporter in adipocytes have elevated lipogenesis and increased glucose tolerance despite being obese with elevated circulating fatty acids. Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (FAHFAs) that were elevated 16- to 18-fold in these mice. FAHFA isomers differ by the branched ester position on the hydroxy fatty acid (e.g., palmitic-acid-9-hydroxy-stearic-acid, 9-PAHSA). PAHSAs are synthesized in vivo and regulated by fasting and high-fat feeding. PAHSA levels correlate highly with insulin sensitivity and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowers ambient glycemia and improves glucose tolerance while stimulating GLP-1 and insulin secretion. PAHSAs also reduce adipose tissue inflammation. In adipocytes, PAHSAs signal through GPR120 to enhance insulin-stimulated glucose uptake. Thus, FAHFAs are endogenous lipids with the potential to treat type 2 diabetes.

SUBMITTER: Yore MM

PROVIDER: S-EPMC4260972 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.

Yore Mark M MM Syed Ismail I Moraes-Vieira Pedro M PM Zhang Tejia T Herman Mark A MA Homan Edwin A EA Patel Rajesh T RT Lee Jennifer J Chen Shili S Peroni Odile D OD Dhaneshwar Abha S AS Hammarstedt Ann A Smith Ulf U McGraw Timothy E TE Saghatelian Alan A Kahn Barbara B BB

Cell 20141001 2

Increased adipose tissue lipogenesis is associated with enhanced insulin sensitivity. Mice overexpressing the Glut4 glucose transporter in adipocytes have elevated lipogenesis and increased glucose tolerance despite being obese with elevated circulating fatty acids. Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (FAHFAs) that were elevated 16- to 18-fold in these mice. FAHFA isomers differ by the branched ester position on the hyd ...[more]

PMID: 25303528

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Project description:Endogenous retroviruses (ERVs) are the remnants of past retroviral infections. Fossil records of class II retroviruses have been discovered in a range of vertebrates, with the exception of amphibians, which are known only to possess class I and class III-like ERVs. Through genomic mining of all available amphibian genomes, we identified, for the first time, class II ERVs in amphibians. The class II ERVs were found only in Gymnophiona (caecilians) and not in the genomes of the other amphibian orders, Anura (frogs and toads) and Caudata (salamanders and newts), which are phylogenetically closely related. Therefore, the ERV endogenization occurred after the split of Gymnophiona, Anura, and Caudata (323 million years ago). Investigation of phylogenetic relationship and genomic structure revealed that the ERVs may originate from alpha- or betaretroviruses. We offer evidence that class II ERVs infiltrated amphibian genomes recently and may still have infectious members. Remarkably, certain amphibian class II ERVs can be expressed in diverse tissues. This discovery closes the major gap in the retroviral fossil record of class II ERVs and provides important insights into the evolution of class II ERVs in vertebrates.IMPORTANCE Class II retroviruses, largely distributed among mammals and birds, are of particular importance for medicine and economics. Class II ERVs have been discovered in a range of vertebrates, with the exception of amphibians, which are known only to possess class I and class III-like ERVs. Here, for the first time, we discovered class II ERVs in amphibians. We also revealed that the ERVs may originate from alpha- or betaretroviruses. We revealed that class II ERVs were integrated into amphibian genomes recently and certain amphibian class II ERVs can be expressed in diverse tissues. Our discovery closes the major gap in the retroviral fossil record of class II ERVs, and also indicates that amphibians may be still infected by class II retroviruses.

Project description:BackgroundMesenchymal stem cells (MSCs) exert anti-diabetic effects and improve long-term complications via secretory effects that regulate macrophage polarisation and attenuate inflammation. Enhancing the efficacy of MSCs needs to be explored further. The in vitro culture microenvironment influences the secretory profile of MSCs. Therefore, we hypothesised that a diabetic microenvironment would promote the secretion of cytokines responsible for macrophage polarisation, further attenuating systemic inflammation and enhancing the effects of MSCs on type 2 diabetes (T2D) and long-term diabetic complications.MethodsPreconditioned adipose-derived mesenchymal stem cells (pre-ADSCs) were obtained after co-cultivating ADSCs in a diabetic metabolic environment (including high sugar, advanced glycation end-product, and lipopolysaccharides). The regulatory effects of pre-ADSCs on macrophages were observed in vitro. A T2D rat model was induced with a high-fat diet for 32 weeks combined with an intraperitoneal injection of streptozotocin. Sprague-Dawley (SD) rats were divided into four groups: normal group, diabetes without treatment group (PBS), ADSC treatment group, and pre-ADSC treatment group. ADSCs and pre-ADSCs were intravenously administered weekly to SD rats for 6 months, and then glucose homeostasis and long-term diabetic complications were evaluated in each group.ResultsThe secretion of cytokines related to M2 macrophage polarisation (IL-6, MCP-1, etc.) was increased in the pre-ADSC group in the in vitro model. Pre-ADSC treatment significantly maintained blood glucose homeostasis, reduced insulin resistance, promoted islet regeneration, and ameliorated the complications related to diabetes in rats (chronic kidney disease, non-alcoholic steatohepatitis, lung fibrosis, and cataract) compared to the ADSC group (P < 0.05). Additionally, the number of anti-inflammatory M2 macrophage phenotypes was enhanced in tissues following pre-ADSC injections. Moreover, the expression of pro-inflammatory genes (iNOS, TNF-α, IL-1β) was reduced whereas that of anti-inflammatory genes (Arg1, CD206, and Il-10) was increased after cultivation with pre-ADSCs.ConclusionDiabetic microenvironment-preconditioned ADSCs effectively strengthen the capacity against inflammation and modulate the progress of long-term T2D complications.

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Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.

Publications

Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.

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