title: Nonthyrotoxic prevention of diet-induced insulin resistance by 3,5-diiodo-L-thyronine in rats.
abstract: OBJECTIVE
  High-fat diets (HFDs) are known to induce insulin resistance. Previously, we showed that 3,5-diiodothyronine (T2), concomitantly administered to rats on a 4-week HFD, prevented gain in body weight and adipose mass. Here we investigated whether and how T2 prevented HFD-induced insulin resistance.
  
  
  METHODS
  We investigated the biochemical targets of T2 related to lipid and glucose homeostasis over time using various techniques, including genomic and proteomic profiling, immunoblotting, transient transfection, and enzyme activity analysis.
  
  
  RESULTS
  Here we show that, in rats, HFD feeding induced insulin resistance (as expected), whereas T2 administration prevented its onset. T2 did so by rapidly stimulating hepatic fatty acid oxidation, decreasing hepatic triglyceride levels, and improving the serum lipid profile, while at the same time sparing skeletal muscle from fat accumulation. At the mechanistic level, 1) transfection studies show that T2 does not act via thyroid hormone receptor β; 2) AMP-activated protein kinase is not involved in triggering the effects of T2; 3) in HFD rats, T2 rapidly increases hepatic nuclear sirtuin 1 (SIRT1) activity; 4) in an in vitro assay, T2 directly activates SIRT1; and 5) the SIRT1 targets peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC-1α) and sterol regulatory element-binding protein (SREBP)-1c are deacetylated with concomitant upregulation of genes involved in mitochondrial biogenesis and downregulation of lipogenic genes, and PPARα/δ-induced genes are upregulated, whereas genes involved in hepatic gluconeogenesis are downregulated. Proteomic analysis of the hepatic protein profile supported these changes.
  
  
  CONCLUSIONS
  T2, by activating SIRT1, triggers a cascade of events resulting in improvement of the serum lipid profile, prevention of fat accumulation, and, finally, prevention of diet-induced insulin resistance.
authors.affiliation: Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Caserta, Italy.
authors.forename: Pieter
authors.initials: P
authors.lastname: de Lange
authors.forename: Federica
authors.initials: F
authors.lastname: Cioffi
authors.forename: Rosalba
authors.initials: R
authors.lastname: Senese
authors.forename: Maria
authors.initials: M
authors.lastname: Moreno
authors.forename: Assunta
authors.initials: A
authors.lastname: Lombardi
authors.forename: Elena
authors.initials: E
authors.lastname: Silvestri
authors.forename: Rita
authors.initials: R
authors.lastname: De Matteis
authors.forename: Lillà
authors.initials: L
authors.lastname: Lionetti
authors.forename: Maria Pina
authors.initials: MP
authors.lastname: Mollica
authors.forename: Fernando
authors.initials: F
authors.lastname: Goglia
authors.forename: Antonia
authors.initials: A
authors.lastname: Lanni
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D004104:Diiodothyronines / Q000627:therapeutic use*; D020536:Enzyme Activators / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006706:Homeostasis / Q000187:drug effects; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D004041:Dietary Fats; D004104:Diiodothyronines; D020536:Enzyme Activators; D008055:Lipids; D037042:Thyroid Hormone Receptors beta; C030103:3,5-diiodothyronine; C488368:Sirt1 protein, rat; D056564:Sirtuin 1