Abstract
Obesity is a chronic metabolic condition with important public health implications associated with numerous co-morbidities including cardiovascular disease, insulin resistance, and hypertension. The renin angiotensin system (RAS), best known for its involvement in cardiovascular control and body fluid homeostasis has, more recently, been implicated in regulation of energy balance. Interference with the RAS (genetically or pharmacologically) has been shown to influence body weight gain. In this study we investigated the effects of systemic AT1 receptor blockade using losartan on ingestive behaviors and weight gain in diet induced obese (DIO) rats. Prior to losartan administration (30 mg/kg/day) body weight gain remained constant within the DIO animals (3.6 ± 0.3 g/day, n = 8), diet resistant (DR) animals (2.1 ± 0.6 g/day, n = 8) and in the age-matched chow fed control (CHOW) animals (2.8 ± 0.3 g/day, n = 8), Losartan administration abolished body weight gain in animals fed a high fat diet (DIO: -0.4 ± 0.7 g/day, n = 8; and DR: -0.8 ± 0.3 g/day, n = 8) while chow fed animals continued to gain weight (2.2 ± 0.3 g/day, n = 8) as they had previously to oral administration of losartan. This decrease in daily body weight gain was accompanied by a decrease in food intake in the HFD fed animals. Following the removal of losartan, both the DIO and DR animals again showed daily increases in body weight gain and food intake which were similar to control values. Our data demonstrate that oral losartan administration attenuates body weight gain in animals fed a HFD whether the animal is obese (DIO) or not DR while having no effect on body weight gain in age-matched chow fed animals suggesting a protective effect of losartan against body weight gain while on a HFD.
Highlights
Obesity is a chronic metabolic condition with important public health implications associated with numerous co-morbidities including cardiovascular disease, insulin resistance, and hypertension
diet resistant (DR) rats weighed the same as age-matched chow fed controls (DR mean body weight = 571.8 ± 16.5 g, n = 8; chow fed mean body weight = 570.9 ± 18.4 g, n = 8; analysis of variance (ANOVA) p < 0.0001, chow vs DR, ns Tukey post hoc analysis) and weighed significantly less than the rats classified as diet induced obesity (DIO) (DIO vs DR, p < 0.001 Tukey post hoc analysis; see Figure 1)
Losartan administration abolished body weight gain in animals fed a high fat diet (HFD) (DIO and DR, p < 0.001, repeated measures ANOVA) while chow fed animals continued to gain weight as they had prior to oral administration of losartan (p = 0.12, repeated measures ANOVA; see Figures 2 and 3). This decrease in daily body weight gain was accompanied by a decrease in food intake in the HFD fed animals (DIO and DR, p < 0.001, repeated measures ANOVA) while water consumption was not altered (p > 0.05, repeated measures ANOVA; see Figure 4)
Summary
Obesity is a chronic metabolic condition with important public health implications associated with numerous co-morbidities including cardiovascular disease, insulin resistance, and hypertension. Not all animals or people who prefer/consume the HFD become obese, and these subjects are described as diet resistant (DR; Levin et al, 1989; Smith and Ferguson, 2012). The DIO phenotype is only partially explained by increased food intake (Levin et al, 1989); obese animals on a HFD diet develop a resistance to the actions of leptin (El-Haschimi et al, 2000; Lin et al, 2000; Wang et al, 2001; Boyle et al, 2011), an adipokine shown to be a key player in the control of food intake and energy metabolism (see Friedman and Halaas, 1998; Jequier, 2002; Galic et al, 2010 for review)
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