microRNA-205-5p is a modulator of insulin sensitivity that inhibits FOXO function

• Objectives: Hepatic insulin resistance is a hallmark of type 2 diabetes and obesity. Insulin receptor signaling through AKT and FOXO has important metabolic effects that have traditionally been ascribed to regulation of gene expression. However, whether all the metabolic effects of FOXO arise from its regulation of protein-encoding mRNAs is unknown. Methods: To address this question, we obtained expression profiles of FOXO-regulated murine hepatic microRNAs (miRNAs) during fasting and refeeding using mice lacking Foxo1, 3a, and 4 in liver (L-Foxo1,3a, 4). Results: Out of 439 miRNA analyzed, 175 were differentially expressed in Foxo knockouts. Their functions were associated with insulin, Wnt, Mapk signaling, and aging. Among them, we report a striking increase of miR-205-5p expression in L-Foxo1,3a,4 knockouts, as well as in obese mice. We show that miR-205-5p gain-of-function increases AKT phosphorylation and decreases SHIP2 in primary hepatocytes, resulting in FOXO inhibition. This results in decreased hepatocyte glucose production. Consistent with these observations, miR-205-5p gain-of-function in mice lowered glucose levels and improved pyruvate tolerance. Conclusions: These findings reveal a homeostatic miRNA loop regulating insulin signaling, with potential implications for in vivo glucose metabolism.

Subject headings

NATURVETENSKAP  -- Biologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Keyword

Insulin resistance

Type 2 diabetes

Transcriptional regulation

Liver metabolism

Glucose production

Genetics

Publication and Content Type

ref (subject category)

art (subject category)