title: High-fat feeding-induced hyperinsulinemia increases cardiac glucose uptake and mitochondrial function despite peripheral insulin resistance.
abstract: In obesity, reduced cardiac glucose uptake and mitochondrial abnormalities are putative causes of cardiac dysfunction. However, high-fat diet (HFD) does not consistently induce cardiac insulin resistance and mitochondrial damage, and recent studies suggest HFD may be cardioprotective. To determine cardiac responses to HFD, we investigated cardiac function, glucose uptake, and mitochondrial respiration in young (3-month-old) and middle-aged (MA) (12-month-old) male Ldlr(-/-) mice fed chow or 3 months HFD to induce obesity, systemic insulin resistance, and hyperinsulinemia. In MA Ldlr(-/-) mice, HFD induced accelerated atherosclerosis and nonalcoholic steatohepatitis, common complications of human obesity. Surprisingly, HFD-fed mice demonstrated increased cardiac glucose uptake, which was most prominent in MA mice, in the absence of cardiac contractile dysfunction or hypertrophy. Moreover, hearts of HFD-fed mice had enhanced mitochondrial oxidation of palmitoyl carnitine, glutamate, and succinate and greater basal insulin signaling compared with those of chow-fed mice, suggesting cardiac insulin sensitivity was maintained, despite systemic insulin resistance. Streptozotocin-induced ablation of insulin production markedly reduced cardiac glucose uptake and mitochondrial dysfunction in HFD-fed, but not in chow-fed, mice. Insulin injection reversed these effects, suggesting that insulin may protect cardiac mitochondria during HFD. These results have implications for cardiac metabolism and preservation of mitochondrial function in obesity.
authors.affiliation: Methodist Diabetes and Metabolism Institute, Houston, TX, USA.
authors.forename: Anisha A
authors.initials: AA
authors.lastname: Gupte
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Minze
authors.forename: Maricela
authors.initials: M
authors.lastname: Reyes
authors.forename: Yuelan
authors.initials: Y
authors.lastname: Ren
authors.forename: Xukui
authors.initials: X
authors.lastname: Wang
authors.forename: Gerd
authors.initials: G
authors.lastname: Brunner
authors.forename: Mohamad
authors.initials: M
authors.lastname: Ghosn
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cordero-Reyes
authors.forename: Karen
authors.initials: K
authors.lastname: Ding
authors.forename: Domenico
authors.initials: D
authors.lastname: Pratico
authors.forename: Joel
authors.initials: J
authors.lastname: Morrisett
authors.forename: Zheng-Zheng
authors.initials: ZZ
authors.lastname: Shi
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Hamilton
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lyon
authors.forename: Willa A
authors.initials: WA
authors.lastname: Hsueh
mesh_terms: D000367:Age Factors; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000503:physiopathology; D015153:Blotting, Western; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000209:etiology / Q000503:physiopathology; D005947:Glucose / Q000493:pharmacokinetics*; D018698:Glutamic Acid / Q000378:metabolism; D006946:Hyperinsulinism / Q000209:etiology / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000503:physiopathology; D010084:Oxidation-Reduction; D010172:Palmitoylcarnitine / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013311:Streptozocin / Q000494:pharmacology; D019802:Succinic Acid / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D024101:Mitochondrial Proteins; D011973:Receptors, LDL; D010172:Palmitoylcarnitine; D018698:Glutamic Acid; D013311:Streptozocin; D019802:Succinic Acid; D005947:Glucose