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

Diabetes Obes Metab. 2004 Jan;6(1):35-44. doi: 10.1111/j.1463-1326.2004.00312.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / pathology
  • Animals
  • Arcuate Nucleus of Hypothalamus / metabolism*
  • Diet / adverse effects*
  • Dietary Fats / administration & dosage*
  • Energy Intake
  • Energy Metabolism
  • Fatty Acids, Omega-3
  • Fatty Acids, Unsaturated / administration & dosage
  • Gene Expression Regulation*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Neuropeptide Y / biosynthesis
  • Neuropeptide Y / genetics
  • Obesity / etiology
  • Obesity / physiopathology
  • Obesity / prevention & control*
  • Pro-Opiomelanocortin / biosynthesis
  • Pro-Opiomelanocortin / genetics
  • RNA, Messenger / genetics
  • Receptors, Cell Surface / biosynthesis
  • Receptors, Cell Surface / genetics
  • Receptors, Leptin
  • Triglycerides / administration & dosage
  • Weight Gain


  • Dietary Fats
  • Fatty Acids, Omega-3
  • Fatty Acids, Unsaturated
  • Neuropeptide Y
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Leptin
  • Triglycerides
  • leptin receptor, mouse
  • Pikasol
  • Pro-Opiomelanocortin