Role of fat amount and type in ameliorating diet-induced obesity: insights at the level of hypothalamic arcuate nucleus leptin receptor, neuropeptide Y and pro-opiomelanocortin mRNA expression

Aims: Dietary fatty acid profile, independent of caloric percent of fat, is a major regulator of body adiposity. This study examined the effects of dietary fat amount and types on fat storage and hypothalamic gene expression in the mouse model of chronic diet‐induced obesity. Methods: The dietary interventions were in twofold: (1) the obesity was induced by a 13‐week obesogenic fat diet compared with a low‐fat (LF) diet, and (2) the reversibility was tested by using high n‐3 polyunsaturated fat (PUFA) and LF diets. Fifty‐four C57Bl/6 mice were fed a high‐fat (59% in kcal) diet for 13 weeks and then classified as diet‐induced obese (DIO) or diet‐resistant (DR) mice according to upper and lower tertiles of body weight gain. The DIO mice were then subdivided into three groups for a 6‐week secondary dietary intervention. Two of the groups were switched to either a high n‐3 PUFA (DIO‐n3) or a low‐fat (10% in kcal, DIO‐LF) diet, whereas the third (controls) and DR mice continued on the initial high‐fat diet. Food efficiency was calculated as weekly body weight gain per gram of food intake. Results: After switching the DIO mice to the n‐3 PUFA or LF diet, their body weights were reduced to the level of the DR and LF mice. The food efficiencies were, from the highest to lowest, in the order: DIO > LF > DR > DIO‐LF > DIO‐n3. Using quantitative in situ hybridization, we found that the DIO mice had higher levels of leptin receptor (LR, +290%, p < 0.005) and neuropeptide Y (NPY, +25%, p < 0.05) mRNA expression in the hypothalamic arcuate nucleus (Arc) than the DR mice, whereas the level of pro‐opiomelanocortin (POMC) mRNA expression was significantly reduced (?45%, p < 0.01). All effects that were essentially returned to DR levels by the change to the n‐3 PUFA diet and, with the exception of a failure to normalize Arc NPY mRNA levels, by the change to LF diet. Conclusions: Taken together, the present results show that both change in level and quality of dietary fat can potently alter hypothalamic neuropeptide expression and result in effective amelioration of diet‐induced obesity. Interestingly, the n‐3 PUFA diet when fed to already obese mice produced a pattern of hypothalamic gene expression similar to that in obesity resistant (DR) mice. It remains to be determined if the effects of n‐3 fatty acids on brain neuropeptide gene expression are direct or indirect.