Complete Resistance to High Fat Diet-Induced Obesity in WSB/EiJ Mice

Abstract

WSB/EiJ (WSB) is a novel wild-derived inbred mouse strain that is genetically distinct from the commonly used strains. Over 50% of the known genetic variation in mice occurs only in wild-derived strains and is not found in the classical strains. We have previously shown that in contrast to C57BL/6J (B6) mice, WSB mice are remarkably resistant to the effects of a high fat and sugar diet (60% fat, 20% sugar). WSB mice eating the high fat diet for over 6 months do not gain any excess weight or fat compared to their chow-fed littermates. The goal of the present studies was to determine the mechanism by which WSB mice are resistant to diet-induced obesity. These studies found that high fat-fed WSB mice lack the hyperphagic response to a high fat diet that is observed in B6 mice and in many humans. However, their total daily caloric intake is similar to high fat-fed B6 mice, which rapidly gain weight. WSB mice have increased energy expenditure compared to B6 mice, but less daily physical activity. An 8 to 32 fold elevation in Ucp1 expression was detected in white adipose tissue in WSB mice, suggesting they have increased “browning” of white adipose tissue that could account for their energy expenditure. WSB mice are also resistant to high fat diet-induced metabolic complications such as insulin resistance and the development of a fatty liver. These studies have identified WSB mice as a model of extreme resistance to a high fat diet, due to increased energy expenditure and the lack of high fat diet-induced hyperphagia. Discovery of the molecular mechanisms underlying this will provide important insight for the development of therapies to prevent and treat obesity.