Angiopoietin-like 2, a circadian gene, improves type 2 diabetes through potentiation of insulin sensitivity in mice adipocytes.

Abstract	Angiopoietin-like (Angptl)2, a member of the Angptl protein family, is predominantly secreted from adipose tissue and the heart. Here, we demonstrate that the expression of Angptl2 in epididymal adipose tissue of C57BL/6J mice shows pulsatility and circadian rhythmicity and that the rhythmicity was disrupted in high-fat-fed and leptin receptor-deficient diabetic db/db mice with insulin resistance. To investigate whether the reduction in Angptl2 expression was related to the progression of diabetes, we treated db/db mice with recombinant Angptl2 for 4 wk during the peak period of Angptl2 expression in C57BL/6J mice. Angptl2-treated mice showed decreases in plasma glucose, insulin, triglyceride, and fatty acid levels and an increase in plasma adiponectin, a therapeutic regulator of insulin resistance, leading to improvements in glucose tolerance. In cultured adipocytes, recombinant Angptl2 increased adiponectin expression and stimulated insulin sensitivity partially by reducing the levels of tribbles homolog 3, a specific Akt kinase inhibitory protein. Conversely, Angptl2 small interfering RNA reduced adiponectin expression, resulting in insulin resistance. In preadipocytes, treatment with Angptl2 small interfering RNA inhibited differentiation to adipocytes and reduced adiponectin expression. Taken together, our results suggest that replenishment of Angptl2 stimulates insulin sensitivity and improves the type 2 diabetic state.
Authors	Masashi Kitazawa, Mamoru Nagano, Koh-Hei Masumoto, Yasufumi Shigeyoshi, Tohru Natsume, Seiichi Hashimoto
Journal	Endocrinology (Endocrinology) Vol. 152 Issue 7 Pg. 2558-67 (Jul 2011) ISSN: 1945-7170 [Electronic] United States
PMID	21586562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	ANGPTL2 protein, human Adiponectin Adipoq protein, mouse Angiopoietin-Like Protein 2 Angiopoietin-like Proteins Angiopoietins Angptl2 protein, mouse Cell Cycle Proteins Circadian Rhythm Signaling Peptides and Proteins Hypoglycemic Agents RNA, Messenger RNA, Small Interfering Receptors, Leptin Recombinant Proteins TRB3 protein, mouse leptin receptor, mouse
Topics	3T3-L1 Cells Adipocytes (cytology, metabolism) Adipogenesis Adiponectin (blood, genetics, metabolism) Angiopoietin-Like Protein 2 Angiopoietin-like Proteins Angiopoietins (antagonists & inhibitors, genetics, metabolism, therapeutic use) Animals Cell Cycle Proteins (genetics, metabolism) Circadian Rhythm Circadian Rhythm Signaling Peptides and Proteins (antagonists & inhibitors, genetics, metabolism, therapeutic use) Diabetes Mellitus, Type 2 (blood, drug therapy, metabolism) Gene Expression Regulation Hypoglycemic Agents (therapeutic use) Insulin Resistance Male Mice Mice, Inbred C57BL Mice, Mutant Strains RNA, Messenger (metabolism) RNA, Small Interfering Receptors, Leptin (genetics, metabolism) Recombinant Proteins (therapeutic use)

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