Infrequent Feeding of Restricted Amounts of Food Induces Stress and Adipose Tissue Inflammation, Contributing to Impaired Glucose Metabolism.

Food restriction has been recommended as an effective strategy for body weight loss. However, food restriction can alter biological rhythms and leads to physiological stress. However, relatively little is known about the physiological impact of different methods of food restriction. Therefore, we investigated whether different schedules of restricted food intake induce physiological stress and then contribute to glucose metabolism disorder. C57BL/6 mice were fed a high fat diet (60% fat) for 8 weeks and then randomly divided into three groups: the control group was continuously fed the high fat diet; the two food restriction groups were fed 50% of food consumed by the control mice with one group (FR1) being fed the full amount once a day and the other group (FR2) being fed the same total amount as FR1 twice a day for 3 days. We found increased body weight loss, the serum triglyceride levels, the expression of lipolysis-related genes, and serum corticosterone levels in the FR1 group compared with the FR2 group. The immune cell population infiltrating the adipose tissue and the expression of monocyte chemoattractant protein (MCP-1) and toll-like receptor (TLR-4) mRNA were increased in the FR1 group compared with the control. To determine whether long-term dietary manipulation is associated with metabolic disorders, mice were fed a restricted diet for 3 days alternating with an unrestricted diet for the following 4 days and this was repeated for 8 weeks. The alternating FR1 group showed impaired glucose tolerance compared with the alternating FR2 group. These results indicate that infrequent feeding of restricted amounts of food could induce stress hormones, lipolysis, adipose tissue immune cell infiltration and inflammation, which in turn may promote glucose metabolism disorder.

Glucagon-Like Peptide 1 Increases ß-Cell Regeneration by Promoting α- to ß-Cell Transdifferentiation.

Glucagon-like peptide 1 (GLP-1) can increase pancreatic ß-cells, and α-cells could be a source for new ß-cell generation. We investigated whether GLP-1 increases ß-cells through α-cell transdifferentiation. New ß-cells originating from non-ß-cells were significantly increased in recombinant adenovirus expressing GLP-1 (rAd-GLP-1)-treated RIP-CreER;R26-YFP mice. Proliferating α-cells were increased in islets of rAd-GLP-1-treated mice and αTC1 clone 9 (αTC1-9) cells treated with exendin-4, a GLP-1 receptor agonist. Insulin+glucagon+ cells were significantly increased by rAd-GLP-1 or exendin-4 treatment in vivo and in vitro. Lineage tracing to label the glucagon-producing α-cells showed a higher proportion of regenerated ß-cells from α-cells in rAd-GLP-1-treated Glucagon-rtTA;Tet-O-Cre;R26-YFP mice than rAd producing ß-galactosidase-treated mice. In addition, exendin-4 increased the expression and secretion of fibroblast growth factor 21 (FGF21) in αTC1-9 cells and ß-cell-ablated islets. FGF21 treatment of ß-cell-ablated islets increased the expression of pancreatic and duodenal homeobox-1 and neurogenin-3 and significantly increased insulin+glucagon+ cells. Generation of insulin+glucagon+ cells by exendin-4 was significantly reduced in islets transfected with FGF21 small interfering RNA or islets of FGF21 knockout mice. Generation of insulin+ cells by rAd-GLP-1 treatment was significantly reduced in FGF21 knockout mice compared with wild-type mice. We suggest that GLP-1 has an important role in α-cell transdifferentiation to generate new ß-cells, which might be mediated, in part, by FGF21 induction.