High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism

Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):3138-3143. doi: 10.1073/pnas.1713837115. Epub 2018 Mar 5.


Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase-fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome.

Keywords: NAFLD; fructose; metabolic syndrome; obesity; salt.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Diabetes Mellitus / chemically induced
  • Fructokinases / genetics
  • Fructose / metabolism*
  • Humans
  • Leptin / blood*
  • Leptin / genetics
  • Metabolic Syndrome / chemically induced
  • Metabolic Syndrome / genetics
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / chemically induced*
  • Obesity / chemically induced*
  • Obesity / metabolism
  • Sodium Chloride, Dietary / adverse effects*
  • Sucrose / adverse effects
  • Sucrose / analogs & derivatives
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Leptin
  • Nfat5 protein, mouse
  • Sodium Chloride, Dietary
  • Transcription Factors
  • Fructose
  • Sucrose
  • trichlorosucrose
  • Fructokinases
  • fructokinase