Enhancing Insulin Secretion by the Novel Adipokine Glypican-4
Final Report Abstract
Obesity and the metabolic syndrome are major challenges for our health and health care system. Increasing evidence points to a central role of adipose tissue in regulating whole body insulin sensitivity by its ability to store excessive energy in form of fat and by acting as important endocrine organ. In this, context we previously showed that the adipose tissue expression and serum levels of the cell surface proteoglycan Glypican-4 strongly correlate with body fat content and whole body insulin sensitivity. In previous studies we found that the whole body knockout Glypican-4 mice blunted glucose stimulated insulin secretion from pancreatic beta cells. In this project we therefore tested if adipose or beta cell expressed Glypican-4 regulates insulin secretion and insulin sensitivity. In contrast to our initial hypothesis we could not find evidence that adipose tissue derived Glypican-4 amplifies glucose stimulated insulin secretion. However, we observed that loss of Glypican-4 from pancreatic beta cells impairs glucose stimulated insulin secretion, albeit this did not appear to be a cell autonomous effect, as in vitro insulin secretion tests did not reveal differences between wildtype and Glypican-4 deficient islets. Surprisingly, however, adipose specific loss of Glypican-4 resulted in elevated high fat diet induced weight gain and insulin resistance compared to littermate controls. Elevated weight gain was not associated with changes in food intake, activity or lipolysis in adipose tissues. But the phenotype was accompanied by increased adipocyte size and adipose inflammation. Interestingly, we also observed increased inflammation in chow diet fed Glypican-4 adipose specific knockout mice, albeit we did not observe signs of local or systemic insulin resistance. Thus, in contrast to a popular hypothesis, at least in our model, insulin resistance is not solely dependent on adipose inflammation but requires adipocyte hypertrophy in addition. Analysis of brown adipose tissue revealed impaired mitochondrial function and cold intolerance in chow but not high fat diet fed mice. However, UCP-1 protein levels were increased in high fat diet fed Glypican-4 adipose-knockout mice and cold tolerance was restored. Moreover, brown adipose specific knockout of Glyipcan-4 resulted in increased whole body energy expenditure and increased UCP-1 protein levels but no differences in high fat diet induced weight gain compared to littermate control mice. Thus, loss of Glypican- 4 in brown adipose tissue could not explain the increased weight gain in adipose deficient Glypican-4 mice, suggesting that the elevated weight gain is the result of a complex interaction between adipose tissue and other organs. In summary, we find that Glypican-4 plays an unexpected role in regulating diet induced weight gain through the modulation of energy expenditure in organs outside the adipose tissue and insulin secretion from pancreatic beta cells.
Publications
- (2018) Chronic D-serine supplementation impairs insulin secretion, Molecular Metabolism, Oct;16:191-202
Suwandhi L, Hausmann S, Braun A, Gruber T, Heinzmann SS, Galvez EJC, Buck A, Israel A, Feuchtinger A, Haythorne E, Staiger H, Heni M, Haring HU, Schmitt-Kopplin P, Walch A, Garcia Caceres C, Rutter GA, Strowig T, Elsner M, Ussar S
(See online at https://doi.org/10.1016/j.molmet.2018.07.002) - (2018) Heterogeneity of adipose tissue in development and metabolic function Journal of Experimental Biology
Schoettl T, Fischer IP, Ussar S
(See online at https://doi.org/10.1242/jeb.162958)
