Angiopoietin-related growth factor antagonizes obesity and insulin resistance

Abstract

Angiopoietin-related growth factor (AGF), a member of the angiopoietin-like protein (Angptl) family, is secreted predominantly from the liver into the systemic circulation. Here, we show that most (>80%) of the AGF-deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. In parallel, mice with targeted activation of AGF show leanness and increased insulin sensitivity resulting from increased energy expenditure. They are also protected from high-fat diet-induced obesity, insulin resistance and nonadipose tissue steatosis. Hepatic overexpression of AGF by adenoviral transduction, which leads to an approximately 2.5-fold increase in serum AGF concentrations, results in a significant (P < 0.01) body weight loss and increases insulin sensitivity in mice fed a high-fat diet. This study establishes AGF as a new hepatocyte-derived circulating factor that counteracts obesity and related insulin resistance.

Association between angiopoietin-like 6 (ANGPTL6) gene polymorphisms and metabolic syndrome-related phenotypes in the French MONICA Study

“…Although Oike et al showed that Angptl6 is involved in fat metabolism and may counteract obesity in mice [14], we detected no significant association between ANGPTL6 polymorphisms and body-weight-related variables in the French MONICA sample. This was not because of a lack of power as, even when considering the most rare allele (frequency 0.09), we would have detected a 0.7 kg/m 2 difference in mean BMI in our study.…”

“…Nevertheless, our findings could be consistent with a physiological role of Angptl6 in terms of insulin sensitivity and glucose metabolism as reported by Oike et al in transgenic mice [14]. Also, it has recently been shown that Angptl6 inhibits glucose production in rat hepatocytes by preventing expression of glucose-6-phosphatase, a key enzyme in gluconeogenesis [22].…”

“…ANGPTL6 was first identified in 2003, and has been characterized as an angiogenic factor involved in epidermal proliferation and wound healing [9,13]. Recently, it was shown that ANGPTL6 is involved in the development of obesity and its related insulin resistance in mouse models [14]. Indeed, Oike et al have shown that mice surviving deletion of the Angptl6 gene develop marked obesity, characterized by an increase in fat depots and adipocyte size, hypercholesterolaemia, elevated plasma non-esterified fatty acid (NEFA) levels, hyperinsulinaemia and glucose intolerance.…”

“…The increased fat mass was due to a decrease in energy expenditure rather than an increase in food intake. In addition, transgenic mice in which Angptl6 was overexpressed displayed a significant reduction in body weight (resulting from increased energy expenditure) and improved insulin sensitivity [14]. These mice were also protected against high-fat diet-induced obesity and non-adiposetissue steatosis.…”

Angiopoietin-Like Proteins Potential Therapeutic Targets for Metabolic Syndrome and Cardiovascular Disease

“…1,9,[15][16][17][18][19] Whereas angiopoietins act via the Tie2 receptor tyrosine kinase, the signaling of which regulates vascular stabilization and remodeling, Angptls do not bind to either Tie2 or the related Tie1 receptor, suggesting that these orphan ligands function differently from angiopoietins. Although several studies show that Angptls potently regulate angiogenesis, 11,20 as do angiopoietins, some Angptls also possess pleiotropic activities other than angiogenesis, such as inhibition of lipoprotein lipase and endothelial lipase, 19,20 augmentation of energy expenditure, 19,21 and induction of inflammation. 22 Lifestyle changes in developed and developing countries, such as inactivity and overnutrition, have lead to the recent increase in the incidence of obesity, which is creating an exploding medical and social problem.…”