Reduced capacity for fatty acid oxidation in rats with inherited susceptibility to diet-induced obesity

Abstract

High-fat, energy-dense diets promote weight gain and obesity in humans and other animals, but the mechanisms underlying such diet-induced obesity remain elusive. To determine whether a reduced capacity to oxidize fat is involved in the etiology of diet-induced obesity, we examined different measures of fatty acid oxidation in rats selectively bred for susceptibility (DIO) or resistance (DR) to dietary obesity before and after they were fed a high-fat diet and became obese. DIO rats eating a low-fat diet oxidized less dietary fatty acid in vivo and had lower levels of plasma ketone bodies during fasting compared with DR rats. Lean DIO rats fed a low-fat diet showed reduced liver messenger RNA expression of CD36, which transports fatty acids across cell membranes, and long-chain acyl-coenzyme A dehydrogenase (ACADL), which catalyzes the first step in the mitochondrial β-oxidation of fatty acids. The deficit in CD36 and ACADL messenger RNA expression was also seen in obese DIO rats that had been eating a high-fat diet and, in addition, was accompanied by reduced expression of liver carnitine palmitoyl transferase I, the enzyme that mediates transport of long-chain fatty acids into mitochondria. No differences were found in the expression of liver enzymes involved in fat synthesis; however, in muscle, DIO rats fed the low-fat, but not high-fat, diet showed greater expression of diacylglycerol O-acyltransferase 1 and lipoprotein lipase than did DR rats. Expression of muscle enzymes involved in fatty acid oxidation was similar in the 2 groups. These findings provide a metabolic mechanism for the development of diet-induced obesity and thus suggest potential targets for intervention strategies to treat or prevent it.

Introduction

Obesity is a rapidly growing public health problem worldwide [1], and consumption of energy-dense foods rich in fat and carbohydrate is considered an important contributing cause [2], [3]. The mechanisms underlying diet-induced obesity remain unclear but are at least partially inherited. Weight gain due to high-fat intake is influenced by a genetic predisposition in humans [4] and varies considerably among different strains of rodents [5], [6]. In arguably the clearest demonstration that predisposition to diet-induced obesity is a heritable trait, Ricci and Levin [7] have selectively bred 2 rat substrains that are either prone (DIO) or resistant (DR) to obesity associated with eating a high-fat diet.

Several lines of evidence suggest that a reduced capacity to oxidize fat may contribute to the etiology of diet-induced obesity and the overeating that usually accompanies it. Previously obese humans oxidize less fat after a fat meal than do lean controls [8], and low rates of fat oxidation predict weight gain in Pima Indians [9] and other populations [10]. There is a strong inverse correlation between fat oxidation in rats eating a low-fat diet and subsequent weight gain after they are switched to a high-fat diet [11], [12]. Pharmacologic inhibition of hepatic fatty acid oxidation stimulates food intake in lean humans and rats eating a high-fat diet [13], whereas stimulation of hepatic fatty acid oxidation reduces food intake, weight gain, and adiposity in rats with diet-induced obesity [12].

In the present experiments, we sought to determine whether there is a preexisting impairment in fatty acid oxidation in DIO rats that would render them less capable of oxidizing dietary fat and thereby more susceptible to diet-induced obesity. To accomplish this, we measured in vivo fatty acid oxidation and messenger RNA (mRNA) expression of enzymes involved in fat metabolism in DIO and DR rats when they were maintained on a low-fat diet, before the DIO rats had an opportunity to become obese. Messenger RNA expression was also measured in rats after they were fed a high-fat diet.