Abstract
Elevated free fatty acids (FFAs) impair beta cell function and reduce beta cell mass as a consequence of the lipotoxicity that occurs in type 2 diabetes (T2D). We previously reported that the membrane protein caveolin-1 (CAV1) sensitizes to palmitate-induced apoptosis in the beta pancreatic cell line MIN6. Thus, our hypothesis was that CAV1 knock-out (CAV1 KO) mice subjected to a high fat diet (HFD) should suffer less damage to beta cells than wild type (WT) mice. Here, we evaluated the in vivo response of beta cells in the pancreatic islets of 8-week-old C57Bl/6J CAV1 KO mice subjected to a control diet (CD, 14% kcal fat) or a HFD (60% kcal fat) for 12 weeks. We observed that CAV1 KO mice were resistant to weight gain when on HFD, although they had high serum cholesterol and FFA levels, impaired glucose tolerance and were insulin resistant. Some of these alterations were also observed in mice on CD. Interestingly, KO mice fed with HFD showed an adaptive response of the pancreatic beta cells and exhibited a significant decrease in beta cell apoptosis in their islets compared to WT mice. These in vivo results suggest that although the CAV1 KO mice are metabolically unhealthy, they adapt better to a HFD than WT mice. To shed light on the possible signaling pathway(s) involved, MIN6 murine beta cells expressing (MIN6 CAV) or not expressing (MIN6 Mock) CAV1 were incubated with the saturated fatty acid palmitate in the presence of mitogen-activated protein kinase inhibitors. Western blot analysis revealed that CAV1 enhanced palmitate-induced JNK, p38 and ERK phosphorylation in MIN6 CAV1 cells. Moreover, all the MAPK inhibitors partially restored MIN6 viability, but the effect was most notable with the ERK inhibitor. In conclusion, our results suggest that CAV1 KO mice adapted better to a HFD despite their altered metabolic state and that this may at least in part be due to reduced beta cell damage. Moreover, they indicate that the ability of CAV1 to increase sensitivity to FFAs may be mediated by MAPK and particularly ERK activation.
Highlights
The western lifestyle, characterized by sedentarism and fat-rich diets, has positioned obesity and its complications amongst the most important public health problems worldwide
After 12 weeks of control (CD) or high fat diet (HFD), progressive weight gain was observed in all mice, because they continued to grow due to their age (Figure 1a)
Only the wild type (WT) mice fed on HFD showed a significant weight gain as compared with WT on control diet (CD), reaching an average body weight of 15.5 ± 5.2 vs. 7.02 ± 2.1 g (p < 0.001), respectively
Summary
The western lifestyle, characterized by sedentarism and fat-rich diets, has positioned obesity and its complications amongst the most important public health problems worldwide. The pathogenesis of T2D is complex and involves, on the one hand, hereditary genetic factors and, on the other hand, external environmental factors (sedentarism, high fat diet, etc.). Two main components are thought to converge in the development of T2D, namely insulin resistance and beta cell dysfunction and death [2]. One of the principal factors involved in beta cell dysfunction and death is the lipotoxicity induced by free fatty acids. Many studies are available addressing the phenomenon of insulin resistance due to lipotoxicity, and the contribution to beta cell dysfunction is well established, the underlying mechanisms in this case are less well understood. T2D develops only in individuals that are unable to sustain this compensatory response, and T2D development coincides with a progressive loss of pancreatic beta cell mass by apoptosis [5]; the factors involved are still a matter of debate
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