MicroRNAs have emerged as essential regulators of beta-cell function and beta-cell proliferation. One of these microRNAs, miR-132, is highly induced in several obesity models and increased expression of miR-132 in vitro modulates glucose-stimulated insulin secretion. The aim of this study was to investigate the therapeutic benefits of miR-132 overexpression on beta-cell function in vivo. To overexpress miR-132 specifically in beta-cells, we employed adeno-associated virus (AAV8) mediated gene transfer using the rat insulin promoter in a double-stranded, self-complementary AAV vector to overexpress miR-132. Treatment of mice with dsAAV8-RIP-mir132 increased miR-132 expression in beta-cells without impacting expression of miR-212 or miR-375. Surprisingly, overexpression of miR-132 did not impact glucose homeostasis in chow fed animals. Overexpression of miR-132 did improve insulin secretion and hence glucose homeostasis in high-fat diet fed mice. Furthermore, miR-132 overexpression increased beta-cell proliferation in mice fed a high-fat diet. In conclusion, our data show that AAV8-mediated gene transfer of miR-132 to beta-cells improves beta-cell function in mice in response to a high fat diet. This suggests that increased miR-132 expression is beneficial for beta-cell function during hyperglycemia and obesity.
Niels L. Mulder, Rick Havinga, Joost L. Kluiver, Albert K Groen and Janine K. Kruit
Hannah M Eggink, Lauren L Tambyrajah, Rosa van den Berg, Isabel M Mol, Jose K van den Heuvel, Martijn Koehorst, Albert K Groen, Anita Boelen, Andries Kalsbeek, Johannes A Romijn, Patrick C N Rensen, Sander Kooijman and Maarten R Soeters
Bile acids can function in the postprandial state as circulating signaling molecules in the regulation of glucose and lipid metabolism via the transmembrane receptor TGR5 and nuclear receptor FXR. Both receptors are present in the central nervous system, but their function in the brain is unclear. Therefore, we investigated the effects of intracerebroventricular (i.c.v.) administration of taurolithocholate (tLCA), a strong TGR5 agonist, and GW4064, a synthetic FXR agonist, on energy metabolism. We determined the effects of chronic i.c.v. infusion of tLCA, GW4064, or vehicle on energy expenditure, body weight and composition as well as tissue specific fatty acid uptake in mice equipped with osmotic minipumps. We found that i.c.v. administration of tLCA (final concentration in cerebrospinal fluid: 1 μM) increased fat oxidation (tLCA group: 0.083 ± 0.006 vs control group: 0.036 ± 0.023 kcal/h, F = 5.46, P = 0.04) and decreased fat mass (after 9 days of tLCA infusion: 1.35 ± 0.13 vs controls: 1.96 ± 0.23 g, P = 0.03). These changes were associated with enhanced uptake of triglyceride-derived fatty acids by brown adipose tissue and with browning of subcutaneous white adipose tissue. I.c.v. administration of GW4064 (final concentration in cerebrospinal fluid: 10 μM) did not affect energy metabolism, body composition nor bile acid levels, negating a role of FXR in the central nervous system in metabolic control. In conclusion, bile acids such as tLCA may exert metabolic effects on fat metabolism via the brain.