Overexpression of human adiponectin in transgenic mice results in suppression of fat accumulation and prevention of premature death by high-calorie diet

Abstract

. Overexpression of human adiponectin in transgenic mice results in suppression of fat accumulation and prevention of premature death by high-calorie diet. Am J Physiol Endocrinol Metab 293: E210-E218, 2007. First published March 27, 2007 doi:10.1152/ajpendo.00645.2006.-Adiponectin, a physiologically active polypeptide secreted by adipocytes, shows insulin-sensitizing, anti-inflammatory, and antiatherogenic properties in rodents and humans. To assess the effects of chronic hyperadiponectinemia on metabolic phenotypes, we established three lines of transgenic mice expressing human adiponectin in the liver. When maintained on a high-fat/high-sucrose diet, mice of two lines that had persistent hyperadiponectinemia exhibited significantly decreased weight gain associated with less fat accumulation and smaller adipocytes in both visceral and subcutaneous adipose tissues. Macrophage infiltration in adipose tissue was markedly suppressed in the transgenic mice. Expression levels of adiponectin receptors were not altered in skeletal muscle or liver. Circulating levels of endogenous adiponectin were elevated, whereas fasting glucose, insulin, and leptin levels were reduced compared with control mice. In the hyperadiponectinemic mice daily food intake was not altered, but oxygen consumption was significantly greater, suggesting increased energy expenditure. Moreover, high-calorie diet-induced premature death was almost completely prevented in the hyperadiponectinemic mice in association with attenuated oxidative DNA damage. The transgenic mice also showed longer life span on a conventional low-fat chow. In conclusion, transgenic expression of human adiponectin blocked the excessive fat accumulation and reduced the morbidity and mortality in mice fed a high-calorie diet. These observations may provide new insights into the prevention and therapy of metabolic syndrome in humans.adipocyte; macrophage; life span; 8-hyroxy-2-deoxyguanosine RESTRICTION OF CALORIC INTAKE retards age-related changes and extends the maximum life span in mammals (22, 37). The longevity is associated with a reduction in steady-state oxidative damage to proteins, lipids, and DNA in animals subjected to restricted caloric intake (13). These decreases in oxidative damage may be attributable to a decrease in the mitochondrial free radical generation rate in various tissues (4). Conversely, obese rats fed a high-calorie diet ad libitum have a shorter life span than their lean counterparts fed a low-calorie diet (36). The excessive production of oxidative stress resulting from high caloric intake may play a role in the premature death.Metabolic syndrome associated with obesity is a growing cause of morbidity and mortality in humans (16, 18). Accumulating evidence has revealed that a reduction in the serum level of adiponectin, a bioactive peptide secreted by adipocytes, is involved in the development of metabolic syndrome and the acceleration of atherosclerosis. The serum level of adiponectin is decreased in patients with obesity (1), type 2 diabetes (17)...

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

“…Transgenic mice overexpressing adiponectin in the liver live longer than controls (Otabe et al ., 2007), suggesting an important role for adiponectin in promoting antiaging and longevity. In our study, plasma adiponectin levels in KO were slightly higher than in WT.…”

“…Particularly under AL fasted conditions, these levels were significantly higher in KO than in WT. Our data were inconsistent with the beneficial phenotypes attributed to higher adiponectin levels in other studies (Otabe et al ., 2007). Plasma adiponectin is composed of a more functional high molecular weight form (HMW) and a less functional low molecular weight form (LMW) (Yamauchi & Kadowaki, 2013).…”

Overexpression of the adiponectin gene mimics the metabolic and stress resistance effects of calorie restriction, but not the anti-tumor effect

“…1C). These findings have already been noted in the original report describing these mice (Otabe, 2007). Adipoq mice are known to increase oxygen consumption rate and decrease body fat content, particularly in response to high calorie diet feeding (Otabe, 2007).…”

“…Pairs of human Adipoq gene overexpressing homozygotic mice and the appropriate wild-type (WT) mice (C57BL/6N) were transferred to the Laboratory animal center at Nagasaki University from Kurume University, where the original SPF colony of Adipoq and WT mice is maintained (Otabe, 2007).…”

“…Increased plasma Adipoq is known to be associated with insulin-sensitizing, anti-diabetic, and anti-atherosclerotic effects (Hui, 2012). Finally, overexpression of the human Adipoq gene is reported to extend the lifespan of mice; not only those fed a high-fat diet (HFD) but also those fed a regular diet (RD: Otabe, 2007).…”