A futile metabolic cycle activated in adipocytes by antidiabetic agents

Nat Med. 2002 Oct;8(10):1122-8. doi: 10.1038/nm780. Epub 2002 Sep 23.


Thiazolidinediones (TZDs) are effective therapies for type 2 diabetes, which has reached epidemic proportions in industrialized societies. TZD treatment reduces circulating free fatty acids (FFAs), which oppose insulin actions in skeletal muscle and other insulin target tissues. Here we report that TZDs, acting as ligands for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma, markedly induce adipocyte glycerol kinase (GyK) gene expression. This is surprising, as standard textbooks indicate that adipocytes lack GyK and thereby avoid futile cycles of triglyceride breakdown and resynthesis from glycerol and FFAs. By inducing GyK, TZDs markedly stimulate glycerol incorporation into triglyceride and reduce FFA secretion from adipocytes. The 'futile' fuel cycle resulting from expression of GyK in adipocytes is thus a novel mechanism contributing to reduced FFA levels and perhaps insulin sensitization by antidiabetic therapies.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipocytes / drug effects*
  • Adipocytes / metabolism*
  • Animals
  • Cell Line
  • Diabetes Mellitus, Type 2 / drug therapy
  • Fatty Acids, Nonesterified / metabolism
  • Gene Expression Regulation
  • Glycerol / metabolism
  • Glycerol Kinase / genetics
  • Glycerol Kinase / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Zucker
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Substrate Cycling
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Transcription Factors / metabolism
  • Triglycerides / metabolism


  • Fatty Acids, Nonesterified
  • Hypoglycemic Agents
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Triglycerides
  • 2,4-thiazolidinedione
  • Glycerol Kinase
  • Glycerol