Glucoraphanin Ameliorates Obesity and Insulin Resistance Through Adipose Tissue Browning and Reduction of Metabolic Endotoxemia in Mice

Diabetes. 2017 May;66(5):1222-1236. doi: 10.2337/db16-0662. Epub 2017 Feb 16.

Abstract

Low-grade sustained inflammation links obesity to insulin resistance and nonalcoholic fatty liver disease (NAFLD). However, therapeutic approaches to improve systemic energy balance and chronic inflammation in obesity are limited. Pharmacological activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) alleviates obesity and insulin resistance in mice; however, Nrf2 inducers are not clinically available owing to safety concerns. Thus, we examined whether dietary glucoraphanin, a stable precursor of the Nrf2 inducer sulforaphane, ameliorates systemic energy balance, chronic inflammation, insulin resistance, and NAFLD in high-fat diet (HFD)-fed mice. Glucoraphanin supplementation attenuated weight gain, decreased hepatic steatosis, and improved glucose tolerance and insulin sensitivity in HFD-fed wild-type mice but not in HFD-fed Nrf2 knockout mice. Compared with vehicle-treated controls, glucoraphanin-treated HFD-fed mice had lower plasma lipopolysaccharide levels and decreased relative abundance of the gram-negative bacteria family Desulfovibrionaceae in their gut microbiomes. In HFD-fed mice, glucoraphanin increased energy expenditure and the protein expression of uncoupling protein 1 (Ucp1) in inguinal and epididymal adipose depots. Additionally, in this group, glucoraphanin attenuated hepatic lipogenic gene expression, lipid peroxidation, classically activated M1-like macrophage accumulation, and inflammatory signaling pathways. By promoting fat browning, limiting metabolic endotoxemia-related chronic inflammation, and modulating redox stress, glucoraphanin may mitigate obesity, insulin resistance, and NAFLD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / drug effects*
  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, White / drug effects*
  • Adipose Tissue, White / metabolism
  • Animals
  • Desulfovibrio
  • Diet, High-Fat
  • Endotoxemia*
  • Energy Metabolism / drug effects
  • Gastrointestinal Microbiome / drug effects
  • Glucosinolates / pharmacology*
  • Imidoesters / pharmacology*
  • Inflammation
  • Insulin Resistance*
  • Lipid Peroxidation / drug effects
  • Lipopolysaccharides / blood
  • Liver / drug effects*
  • Liver / metabolism
  • Macrophages / drug effects
  • Mice
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Obesity / metabolism*
  • Uncoupling Protein 1 / drug effects
  • Uncoupling Protein 1 / metabolism

Substances

  • Glucosinolates
  • Imidoesters
  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • glucoraphanin