CoChat
Sign Up
Cited by 106Adipose Tissue and MetabolismSirtuins and Resveratrol in MedicineThyroid Disorders and Treatments

Nonthyrotoxic Prevention of Diet-Induced Insulin Resistance by 3,5-Diiodo-L-Thyronine in Rats

Open access
de Lange, Pieter, Cioffi, Federica, Senese, Rosalba, Moreno, Maria, Lombardi, Assunta, Silvestri, Elena, De Matteis, Rita, Lionetti, Lillà +3 more·2011·Diabetes
DOI 10.2337/db11-0207PMC PMC3198093
Open this paper in CoChat — free accountOpen PDF

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. RESEARCH DESIGN AND 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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.2337/db11-0207

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 3,5-T2 increases nuclear sirtuin 1 and downregulates lipogenic genes.

    “In addition to its other effects on the liver, 3,5-T2 also increases nuclear sirtuin 1 and downregulates lipogenic genes (De Lange et al. 2011).”

    From Administration of 3,5-diiodothyronine (3,5-T2) causes central hypothyroidism and stimulates thyroid-sensitive tissues (2014) · cites this paper as De Lange et al. 2011

    The Results (Fig. 3; page not supplied) report increased hepatic nuclear SIRT1 activity after T2 treatment, but do not establish an increase in nuclear SIRT1 protein levels. The Results (Fig. 4; page not supplied) report downregulation of the lipogenic genes ACC, FAS and Spot 14 in T2-treated, high-fat-diet rats. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • There have been observations that 3,5-T2 interferes with pancreatic islet function, altering glucagon and insulin expression and secretion.

    “There have also been observations that 3,5-T2 interferes with the function of pancreatic islets altering glucagon and insulin expression and secretion (91, 96).”

    From 3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action (2020) · cites this paper as [91]

    The Methods section reports blood insulin measurements, and the Results and Discussion describe T2 effects on insulin resistance and liver metabolism. Searches for pancreatic islets, glucagon, and insulin secretion found no passage in our copy addressing whether T2 alters islet function or glucagon and insulin expression or secretion. No page numbers were provided for these passages. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 29

  1. [1]Reilly MP Rader DJ. The metabolic syndrome: more than the sum of its parts? Circulation 2003; 108: 1546– 1551 14517150
  2. [2]Barness LA Opitz JM Gilbert-Barness E. Obesity: genetic, molecular, and environmental aspects. Am J Med Genet A 2007; 143A: 3016– 3034 18000969
  3. [3]Oppenheimer JH Schwartz HL Lane JT Thompson MP. Functional relationship of thyroid hormone-induced lipogenesis, lipolysis, and thermogenesis in the rat. J Clin Invest 1991; 87: 125– 132 1985090 PMC295007
  4. [5]Baxter JD Webb P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov 2009; 8: 308– 320 19337272
  5. [6]Cioffi F Lanni A Goglia F. Thyroid hormones, mitochondrial bioenergetics and lipid handling. Curr Opin Endocrinol Diabetes Obes 2010; 17: 402– 407 20625286
  6. [7]Ribeiro MO. Effects of thyroid hormone analogs on lipid metabolism and thermogenesis. Thyroid 2008; 18: 197– 203 18279020
  7. [8]Lanni A Moreno M Lombardi A. 3,5-Diiodo-L-thyronine powerfully reduces adiposity in rats by increasing the burning of fats. FASEB J 2005; 19: 1552– 1554 16014396
  8. [9]Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007; 8: 774– 785 17712357
  9. [10]Baur JA Pearson KJ Price NL. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444: 337– 342 17086191 PMC4990206
  10. [11]Gerhart-Hines Z Rodgers JT Bare O. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 2007; 26: 1913– 1923 17347648 PMC1847661
  11. [13]Picard F Kurtev M Chung N. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004; 429: 771– 776 15175761 PMC2820247
  12. [15]Rodgers JT Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A 2007; 104: 12861– 12866 17646659 PMC1937557
  13. [17]Lionetti L Mollica MP Crescenzo R. Skeletal muscle subsarcolemmal mitochondrial dysfunction in high-fat fed rats exhibiting impaired glucose homeostasis. Int J Obes (Lond) 2007; 31: 1596– 1604 17637704
  14. [18]Mollica MP Lionetti L Moreno M. 3,5-Diiodo-l-thyronine, by modulating mitochondrial functions, reverses hepatic fat accumulation in rats fed a high-fat diet. J Hepatol 2009; 51: 363– 370 19464748
  15. [19]Moreno M Lanni A Lombardi A Goglia F. How the thyroid controls metabolism in the rat: different roles for triiodothyronine and diiodothyronines. J Physiol 1997; 505: 529– 538 9423191 PMC1160082
  16. [20]Alexson SEH Nedergaard J. A novel type of short- and medium-chain acyl-CoA hydrolases in brown adipose tissue mitochondria. J Biol Chem 1988; 263: 13564– 13571 2901416
  17. [21]de Lange P Farina P Moreno M. Sequential changes in the signal transduction responses of skeletal muscle following food deprivation. FASEB J 2006; 20: 2579– 2581 17065218
  18. [22]de Lange P Feola A Ragni M. Differential 3,5,3′-triiodothyronine-mediated regulation of uncoupling protein 3 transcription: role of Fatty acids. Endocrinology 2007; 148: 4064– 4072 17478558
  19. [24]Silvestri E Moreno M Schiavo L. A proteomics approach to identify protein expression changes in rat liver following administration of 3,5,3′-triiodo-L-thyronine. J Proteome Res 2006; 5: 2317– 2327 16944944
  20. [25]Lombardi A Silvestri E Cioffi F. Defining the transcriptomic and proteomic profiles of rat ageing skeletal muscle by the use of a cDNA array, 2D- and Blue native-PAGE approach. J Proteomics 2009; 72: 708– 721 19268720
  21. [26]Solanes G Pedraza N Iglesias R Giralt M Villarroya F. The human uncoupling protein-3 gene promoter requires MyoD and is induced by retinoic acid in muscle cells. FASEB J 2000; 14: 2141– 2143 11024001
  22. [27]Cable EE Finn PD Stebbins JW. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology 2009; 49: 407– 417 19072834
  23. [28]Fulco M Sartorelli V. Comparing and contrasting the roles of AMPK and SIRT1 in metabolic tissues. Cell Cycle 2008; 7: 3669– 3679 19029811 PMC2607479
  24. [29]Cantó C Jiang LQ Deshmukh AS. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 2010; 11: 213– 219 20197054 PMC3616265
  25. [30]Purushotham A Schug TT Xu Q Surapureddi S Guo X Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 2009; 9: 327– 338 19356714 PMC2668535
  26. [31]Ponugoti B Kim D-H Xiao Z. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem 2010; 285: 33959– 33970 20817729 PMC2962496
  27. [32]Banks AS Kon N Knight C. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 2008; 8: 333– 341 18840364 PMC3222897
  28. [33]Lynch CJ Fox H Hazen SA Stanley BA Dodgson S Lanoue KF. Role of hepatic carbonic anhydrase in de novo lipogenesis. Biochem J 1995; 310: 197– 202 7646445 PMC1135873
  29. [34]Supuran CT Di Fiore A De Simone G. Carbonic anhydrase inhibitors as emerging drugs for the treatment of obesity. Expert Opin Emerg Drugs 2008; 13: 383– 392 18537527

Cited by

Sorted by citations

Authors
de Lange, P., Cioffi, F., Senese, R., Moreno, M., Lombardi, A., Silvestri, E., De Matteis, R., Lionetti, L., Mollica, M. P., Goglia, F., & Lanni, A.
Affiliations
  • Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Caserta, Italy
  • University of Sannio (IT)
  • University of Campania "Luigi Vanvitelli" (IT)
  • Dipartimento di Scienze per la Biologia, la Geologia e l’Ambiente, Università degli Studi del Sannio, Benevento, Italy
  • University of Naples Federico II (IT)
  • Dipartimento di Scienze Biomolecolari, Università di Urbino “Carlo Bo,” Urbino, Italy
Corresponding author
  • Goglia, Fernando
  • Lanni, Antonia
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2011-10-17
Volume
60
Issue
11
Pages
2730-2739
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db11-0207
PMC
PMC3198093
OpenAlex
W2102940743
Cited by
106
References
5
Citations by year
2026: 1 · 2025: 1 · 2024: 5 · 2023: 1 · 2022: 7 · 2021: 6 · 2020: 7 · 2019: 12 · 2018: 13 · 2017: 9 · 2016: 9 · 2015: 10 · 2014: 15 · 2013: 7 · 2012: 3
FWCI
5.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
  • CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
Funders
  • University of Minnesota
  • Universitat de Barcelona
Topics
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Keywords
3,5-diiodothyronine, insulin resistance, high-fat diet, hepatic fatty acid oxidation, hepatic triglycerides, lipid profile, SIRT1, PGC-1α, SREBP-1c, mitochondrial biogenesis, hepatic gluconeogenesis, thyroid hormone receptor beta, AMPK
MeSH terms
Animals, Cell Line, Cell Nucleus, Dietary Fats, Diiodothyronines, Gene Expression Regulation, Homeostasis, Insulin Resistance, Lipids, Liver, Male, Weight Gain, Rats, Wistar, Glucose Intolerance, Muscle, Skeletal, Enzyme Activators, Gene Expression Profiling, Thyroid Hormone Receptors beta, Intra-Abdominal Fat, Lipid Metabolism, Rats, Sirtuin 1

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review