Abstract
Obesity is a major disease condition, in turn leading to pathological changes collectively recognized as metabolic syndrome. Recently angiotensin receptor AT2R has been associated negatively with body weight (BW) gain in male mice. However, the gender differences in AT2R and BW changes have not been studied. To understand the gender based role of AT2R involving BW changes, we fed male and female wild type (WT) and AT2R knock out (AT2KO) mice with C57BL6 background with high fat diet (HFD) for 16 weeks. The male AT2KO had higher HFD calorie intake (WT: 1280±80; AT2KO:1680±80 kcal) but gained less BW compared with the WT (WT: 13; AT2KO: 6 g). Contrary to the male animals, the female AT2KO mice with equivalent caloric intake (WT: 1424±48; AT2KO:1456±80 kcal) gained significantly more BW than the WT mice (WT: 9 g; AT2KO: 15 g). The male AT2KO on HFD displayed lower plasma insulin level, less impaired glucose tolerance (GT), and higher plasma T3 compared with WT males on HFD; whereas the female AT2KO mice on HFD showed elevated levels of plasma insulin, more impaired GT, lower plasma T3 and higher free fatty acid and hepatic triglycerides compared with WT females on HFD. Interestingly, compared with WT, AT2KO female mice had significantly lower estrogen, which was further reduced by HFD. These results suggest that AT2R in female mice via potentially regulating estrogen may have protective role against BW gain and impaired glucose tolerance and lipid metabolism.
Highlights
[5] Studies suggest that absence or blockade of AT1aR in mice results in resistance of diet-induced obesity, improvement of glucose tolerance and insulin sensitivity, and protection against some traits of metabolic syndrome. [6,7] Studies using male AT2R knock out (AT2KO) mice have shown a negative relationship between AT2R and body weight gain, implying that absence of AT2R is associated with lower body weight gain.[8,9,10,11]
We found no significant difference in the kcal consumption of normal diet (ND) among the males and females of either wild type (WT) or AT2KO (Figure 1)
We found that AT2KO males on high fat diet (HFD) had lesser body weight gain, lower gonadal adipose depot weight, lower levels of plasma insulin less impaired glucose tolerance (GT), higher plasma T3 and higher urinary estrogen levels, compared with HFD fed WT males
Summary
Obesity by itself is a major disease condition, which, in turn, leads to a host of associated pathological changes collectively recognized as metabolic syndrome. [1] Renin angiotensin system (RAS) in addition to playing a critical role in regulating blood pressure (BP) and maintaining electrolyte balance has been reported to contribute towards the initiation and progression of metabolic syndrome.[2,3,4] Actions of angiotensin II, the major peptide hormone of RAS, are mediated via its two receptors namely AT1R and AT2R. [5] Studies suggest that absence or blockade of AT1aR in mice results in resistance of diet-induced obesity, improvement of glucose tolerance and insulin sensitivity, and protection against some traits of metabolic syndrome. [6,7] Studies using male AT2KO mice have shown a negative relationship between AT2R and body weight gain, implying that absence of AT2R is associated with lower body weight gain.[8,9,10,11] these studies have only included male mice.Gender based differences in both humans and animal models are known to exist with regards to BP regulation, progression of renal damage, inflammation, weight gain and obesity.[12,13,14] These differences have primarily been attributed to changes and alterations by sex hormones. [9] Estrogen in particular has been implicated in rendering female gender specific protection of physiological changes. [15] Further, many of these selective advantages such as glucose intolerance and vasodilatation in females are potentially brought about by interaction of estrogen with other hormones and receptors such as insulin and recently with AT2R. [16,17] Recent evidence indicates a positive role of AT2R in physiological changes by an independent action as well as by influencing interactions with other components of RAS system including AT1R and angiotensin I converting enzyme 2 (ACE2). [15] While the protective role of AT2R in lowering BP in females has been recently reported, [18] the role of AT2R in gender based changes to body weight is not known. While obesity is described as an overall disorder of energy balance resulting from increase in food intake and/or reduced energy expenditure, it is symptomatically characterized by impaired glucose tolerance, hyperinsulinemia and enhanced plasma free fatty acids (FFA) that in turn contributes further towards insulin resistance.[19,20,21] The present study was designed to understand the differential role of AT2R in body weight changes and metabolic parameters between male and female mice. We found that at the end of 16 weeks of high fat diet (HFD), absence of AT2R had opposite effects on the body weight gain, glucose tolerance, and plasma insulin of males and females; and these changes were inversely related to several factors including changes in the estrogen levels, and physiological role of AT2R in males and females
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