Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat

Abstract

In response to moderately increased dietary fat content, melanocortin-4 receptor-null mutant (MC4R-/-) mice exhibit hyperphagia and accelerated weight gain compared to wild-type mice. An increased feed efficiency (weight gain/kcal consumed) argues that mechanisms in addition to hyperphagia are instrumental in causing weight gain. We report two specific defects in coordinating energy expenditure with food intake in MC4R-/- mice. Wild-type mice respond to an increase in the fat content of the diet by rapidly increasing diet-induced thermogenesis and by increasing physical activity, neither of which are observed in MC4R-/- mice. Leptin-deficient and MC3R-/- mice regulate metabolic rate similarly to wild-type mice in this protocol. Melanocortinergic pathways involving MC4-R-regulated neurons, which rapidly respond to signals not requiring changes in leptin, thus seem to be important in regulating metabolic and behavioral responses to dietary fat.

Interactions between the melanocortin system and the hypothalamo–pituitary–thyroid axis

“…In support of these findings, MC4-R null mice are unable to increase oxygen consumption, a marker of energy expenditure, in response to high-fat diet suggesting that the MC4-R is necessary for diet-induced thermogenesis [8]. Similarly, MC4-R null mice are also unable to increase activity-based energy expenditure, shown to make an important contribution to energy balance [43], following increases in dietary fat [8].…”

“…Similarly, MC4-R null mice are also unable to increase activity-based energy expenditure, shown to make an important contribution to energy balance [43], following increases in dietary fat [8].…”

Relevance of animal models to human eating disorders and obesity

“…MC 4 R knockout mice have also implicated the MC 4 R in the obesigenic effects of high-fat diets (Butler et al 2001). …”

“…MC 4 R knockout mice display accelerated weight gain when placed on a diet with increased fat content, due to enhanced hyperphagia and loss of the compensatory increase in metabolic rate and activity in response to high-fat diet consumption (Butler et al 2001). Thus, the MC 4 R knockout mouse is important, as it led to further elucidation of the regulation of body weight by the melanocortin system, identified a potential target for obesity treatment (Butler 2006), and models a relatively common type of human obesity.…”

The genetics of childhood obesity and interaction with dietary macronutrients

“…Moreover, in comparison with Mc4r ?/? mice fed a high-fat diet, the Mc4r -/-mice were found to have hyperphagia and altered energy expenditure characterized by decreased diet-induced activity and thermogenesis (Butler et al 2001;Weide et al 2003). Consistent with these results, the Mc4r -/-mice developed hyperphagia when fed a high-fat diet, but not when fed a low-fat diet, providing evidence for a gene-diet interaction in relation to weight gain (Butler and Cone 2003;Sutton et al 2006).…”