Angiotensin converting enzyme inhibition lowers body weight and improves glucose tolerance in C57BL/6J mice maintained on a high fat diet
Introduction
Obesity is a major risk factor in the development of hypertension, dyslipidemia, hyperglycemia and, therefore, with higher cardiovascular risk [1], [2]. In the US, a recent survey revealed that 9.1% of all medical expenditure was obesity-related illness [3] and data from the 1998 Medical Expenditure panel survey and the 1996 and 1997 National Health Interview Surveys indicate that overweight and obesity cost 78.5 billion dollars annually.
While the classical renin–angiotensin system (RAS) is known for its role in body fluid and cardiovascular homeostasis, there is an analogous RAS located in adipose tissue [4], [5], [6], [7]. The adipose tissue RAS is thought to play a major role in the development of adiposity. For example, angiotensinogen-deficient mice (AGT-KO) gain less weight than their wild-type (WT) counterparts despite similar food intakes [8]. Recently, we have shown that angiotensin converting enzyme-deficient mice (ACE-KO) weighed 20% less and had 50% less body fat than age-matched WT controls [9]. The decreased body fat occurred despite normal food intake and activity levels, and was shown to be due to increased energy expenditure, i.e., increased fatty acid oxidation in the liver. Angiotensin II type 1a (AT1a) receptor-deficient mice [10] and AT2 receptor-deficient mice [11] have also been shown to gain less weight than their wild-type (WT) counterparts when maintained on a high fat diet. The reduced body weight gain of the AT1 receptor or AT2 receptor-deficient mice was attributed to increased energy expenditure with either a normal or decreased food intake. In contrast, transgenic mice that over-express adipose AGT have higher body weight compared with controls. The difference in body weights was due primarily to an increase in total body fat which was due to an increase in adipocyte size. The increased fat mass was not attributable to either differences in food intake or motor activity [12].
Recently, we demonstrated that treatment with perindopril, an ACE inhibitor, from birth, reduced the body fat of Sprague–Dawley rats maintained on a 7% fat diet [13] and of rats with transgenically increased tissue levels of ANG II (TGR mREN2 27) [14]. In mice maintained on a high fat diet, treatment with telmisartan (an AT1 receptor antagonist), decreased visceral adiposity and body weight without altering food intake or locomotor activity [15]. The telmisartan treatment increased UCP1 mRNA, a marker of energy expenditure, in brown adipose tissue, and decreased triglyceride uptake into white adipose tissue, liver and skeletal muscle. Furthermore, telmisartan treatment decreased carbohydrate and increased fat metabolism. In addition to the abovementioned changes, telmisartan treatment increased adiponectin mRNA in white adipose tissue. However, many of the changes caused by telmisartan were attributed to its partial agonist influence on PPARγ given that valsartan failed to produce similar effects [16] and telmisartan increases fatty acid oxidation in muscle via a PPARγ dependent pathway [17], [18].
The purpose of the present study was to investigate the effect of captopril (a drug that interferes with ANG II activity without directly altering PPARγ signalling) on diet-induced obesity and insulin resistance. C57Bl/6J mice, known for their sensitivity to diet-induced obesity [19] were maintained on a high fat diet. The effect of captopril on food and water intakes, body, liver, muscle and adipose tissue weights, glucose tolerance and several hormones and metabolites associated with body weight regulation (leptin, adiponectin, insulin, glucose and non-esterified fatty acids [NEFA]) were determined.
Section snippets
Materials and methods
Male C57BL/6J mice (n = 24) were obtained from Animal Resources Centre (Canning Vale, WA) and housed individually from 8 weeks of age. The animals were housed in the Central Animal House (La Trobe University) with temperatures maintained at 22 °C ± 3 °C and with a 12 h light/dark cycle (lights off at 18:00 h). This study complied with the policy and procedures of the Animal Ethics Committee of La Trobe University.
After an adaptation period of 1 week, body weights were recorded (average = 23.8 ± 3 g)
Body weight
As shown in Fig. 1A, body weights of the two groups were not different at the commencement of the study. Following 2 weeks of treatment, animals receiving captopril had lost weight and were, on average, 20–25% lighter than their pre-treatment weight. Control animals had gained weight and were significantly heavier than captopril-treated animals. Body weights of captopril-treated animals remained lower than their own baseline and lower than control animals for the rest of the study. Control
Discussion
The primary aim of the current work was to evaluate the ability of captopril to prevent diet-induced obesity in obesity prone C57Bl/6J mice. The results clearly demonstrated in animals maintained on a high fat diet that captopril treatment prevented diet-induced obesity and also, surprisingly, caused a large and rapid decrease in body weight. After 2 weeks of treatment, captopril-treated animals weighed approximately 20% less than their own pre-treatment weight. This weight loss was larger and
Acknowledgements
This work was supported by the National Health and Medical Research Council of Australia (grant numbers 217011, 350313, 433021) and the Australian Research Council (grant number DP0346830).
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