Dietary Fat, but Not Protein or Carbohydrate, Regulates Energy Intake and Causes Adiposity in Mice

Cell Metab. 2018 Sep 4;28(3):415-431.e4. doi: 10.1016/j.cmet.2018.06.010. Epub 2018 Jul 12.


The impacts of different macronutrients on body weight regulation remain unresolved, with different studies suggesting increased dietary fat, increased carbohydrates (particularly sugars), or reduced protein may all stimulate overconsumption and drive obesity. We exposed C57BL/6 mice to 29 different diets varying from 8.3% to 80% fat, 10% to 80% carbohydrate, 5% to 30% protein, and 5% to 30% sucrose. Only increased dietary fat content was associated with elevated energy intake and adiposity. This response was associated with increased gene expression in the 5-HT receptors, and the dopamine and opioid signaling pathways in the hypothalamus. We replicated the core findings in four other mouse strains (DBA/2, BALB/c, FVB, and C3H). Mice regulate their food consumption primarily to meet an energy rather than a protein target, but this system can be over-ridden by hedonic factors linked to fat, but not sucrose, consumption.

Keywords: FGF signaling; energy regulation; fat intake; hedonic overdrive; hypothalamic hunger pathway; mTOR signaling; mice; obesity; protein leverage hypothesis; sucrose intake.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity*
  • Analgesics, Opioid / metabolism*
  • Animals
  • Dietary Carbohydrates / metabolism*
  • Dietary Fats / metabolism*
  • Dietary Proteins / metabolism*
  • Dopamine / metabolism*
  • Energy Intake
  • Hypothalamus / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Obesity
  • Receptors, Serotonin / metabolism*
  • Signal Transduction


  • Analgesics, Opioid
  • Dietary Carbohydrates
  • Dietary Fats
  • Dietary Proteins
  • Receptors, Serotonin
  • Dopamine