Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids - PubMed (original) (raw)

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. 2016 Nov;280(5):465-475.

doi: 10.1111/joim.12540. Epub 2016 Oct 3.

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Review

Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids

U Smith et al. J Intern Med. 2016 Nov.

Abstract

Obesity, the major cause of the current global epidemic of type 2 diabetes (T2D), induces insulin resistance in peripheral insulin target tissues. Several mechanisms have been identified related to cross-talk between adipose tissue, skeletal muscle and liver. These mechanisms involve both increased free fatty acid release and altered secretion of adipokines from adipose tissue. A major determinant of metabolic health is the ability of subcutaneous adipose tissue (SAT) to store excess fat rather than allowing it to accumulate in ectopic depots including liver (i.e. in nonalcoholic fatty liver disease), muscle and heart, or in epicardial/pericardial and visceral fat depots which promote the metabolic complications of obesity. The ability to recruit and differentiate precursor cells into adipose cells (adipogenesis) in SAT is under genetic regulation and is reduced in high-risk individuals who have first-degree relatives with T2D. Early recruitment of new adipose cells is dependent on the cross-talk between canonical WNT and BMP4 signalling; WNT enhances their undifferentiated and proliferative state whereas BMP4 induces their commitment to the adipogenic lineage. Dysregulation of these signalling pathways is associated with impaired adipogenesis and impaired ability to respond to the need to store excess lipids in SAT. This leads to hypertrophic, dysfunctional and insulin-resistant adipose cells with a reduced content of GLUT4, the major insulin-regulated glucose transporter, which in turn reduces adipose tissue glucose uptake and de novo lipogenesis. We recently identified that reduced GLUT4 and lipogenesis in adipocytes impairs the synthesis of a novel family of lipids secreted by adipose tissue (and potentially other tissues), branched fatty acid esters of hydroxy fatty acids (FAHFAs). FAHFAs have beneficial metabolic effects, including enhancing insulin-stimulated glucose transport and glucose-stimulated GLP1 and insulin secretion, as well as powerful anti-inflammatory effects. FAHFA levels are reduced in subcutaneous adipose tissue in insulin-resistant individuals, and this novel family of lipids may become of future therapeutic use.

Keywords: adipose tissue; glucose; insulin resistance; lipogenesis; type 2 diabetes.

© 2016 The Association for the Publication of the Journal of Internal Medicine.

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Conflict of interest statement

statement BBK is an inventor on patents regarding RBP4 and FAHFA lipids.

Figures

Fig. 1

Fig. 1

Adipocyte hypertrophy and associated characteristics. IR, insulin resistant; FDR, first-degree relative., AT, adipose tissue Reproduced from Gustafson et al. (52), with permission.

Fig. 2

Fig. 2

Subcutaneous adipose tissue in humans.

Fig. 3

Fig. 3

Structure of branched fatty acid esters of hydroxy fatty acids (FAHFAs). (A) FAHFAs are esters that combine a fatty acid such as palmitate with a hydroxy fatty acid backbone such as hydroxystearic acid. The FAHFA shown is 9-palmitic acid hydroxystearic acid (PAHSA) which is the most upregulated FAHFA family member in adipose tissue of mice that are overexpressing GLUT4 selectively in adipocytes. (B) A total of 16 FAHFA family members were identified in mouse serum. These lipids consist of four different fatty acid moieties and four hydroxy fatty acid moieties in different combinations. Adapted from ref. and reproduced with permission from Cell Press.

Fig 4

Fig 4

Anti-diabetic and anti-inflammatory effects of branched fatty acid esters of hydroxy fatty acids (FAHFAs). (a) Glucose is transported into adipocytes by the GLUT4 glucose transporter. The increased glucose entry activates the transcription factor ChREBP, thereby enhancing de novo lipogenesis and synthesis of branched Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs). (b) FAHFAs augment insulin-stimulated glucose transport in adipocytes and glucose-stimulated GLP1 secretion from the gut enteroendocrine cells and insulin secretion from pancreatic beta cells. FAHFAs also reduce inflammation by decreasing the production of pro-inflammatory cytokines from macrophages and dendritic cells. ChREBP, carbohydrate response element binding protein; FAS, fatty acid synthase; GPR120, G protein-coupled receptor 120. Diabetes: The good in fat. Muoio D.M & Newgard C.B. Nature 516:49–50, 2014. Reproduced with permission from Nature Publishing Group, license number 3851950681929.

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References

    1. IDF Diabetes Atlas. International Diabetes Federation. 7 Brussels, Belgium: 2015.
    1. Li R, Lu W, Jia J, et al. Relationships between indices of obesity and its cardiovascular comorbidities in a Chinese population. Circ J. 2008;72:973–8. - PubMed
    1. The IDF consensus worldwide definition of the metabolic syndrome. International Diabetes Federation; Brussels, Belgium: 2005. Apr 14, http://www.idf.org/webdata/docs/Metac_syndrome_def.pdf.
    1. Perry RJ, Camporez JP, Kursawe R, et al. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell. 2015;160:745–58. - PMC - PubMed
    1. Arner P, Langin D. Lipolysis in lipid turnover, cancer cachexia, and obesity-induced insulin resistance. Trends Endocrinol Metab. 2014;25:255–62. - PubMed

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