title: Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver.
abstract: The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin resistance promotes hepatic TCA cycle flux in mice progressing to insulin resistance and fatty liver on a high-fat diet (HFD) for 32 weeks using standard biomolecular and in vivo (2)H/(13)C tracer methods. Relative mitochondrial content increased, but respiratory efficiency declined by 32 weeks of HFD. Fasting ketogenesis became unresponsive to feeding or insulin clamp, indicating blunted but constitutively active mitochondrial β-oxidation. Impaired insulin signaling was marked by elevated in vivo gluconeogenesis and anaplerotic and oxidative TCA cycle flux. The induction of TCA cycle function corresponded to the development of mitochondrial respiratory dysfunction, hepatic oxidative stress, and inflammation. Thus, the hepatic TCA cycle appears to enable mitochondrial dysfunction during insulin resistance by increasing electron deposition into an inefficient respiratory chain prone to reactive oxygen species production and by providing mitochondria-derived substrate for elevated gluconeogenesis.
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Satapati
authors.forename: Nishanth E
authors.initials: NE
authors.lastname: Sunny
authors.forename: Blanka
authors.initials: B
authors.lastname: Kucejova
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Fu
authors.forename: Tian Teng
authors.initials: TT
authors.lastname: He
authors.forename: Andrés
authors.initials: A
authors.lastname: Méndez-Lucas
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.forename: Jose C
authors.initials: JC
authors.lastname: Perales
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Browning
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Burgess
mesh_terms: D000818:Animals; D019069:Cell Respiration; D002952:Citric Acid Cycle; D059305:Diet, High-Fat / Q000009:adverse effects*; D005234:Fatty Liver / Q000150:complications / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D005943:Gluconeogenesis; D006943:Hyperglycemia / Q000150:complications; D007333:Insulin Resistance; D007657:Ketone Bodies / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000150:complications; D018384:Oxidative Stress; D013997:Time Factors
chemical_list: D007657:Ketone Bodies