Home LiteratureArticle Details
PMID: 16528412 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats.

The Journal of clinical investigation ·Vol. 116 ·No. 4 ·2006-04-00 ·Pages 1081-91

Pocai A, Lam TK, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A, Rossetti L

Abstract

Short-term overfeeding blunts the central effects of fatty acids on food intake and glucose production. This acquired defect in nutrient sensing could contribute to the rapid onset of hyperphagia and insulin resistance in this model. Here we examined whether central inhibition of lipid oxidation is sufficient to restore the hypothalamic levels of long-chain fatty acyl-CoAs (LCFA-CoAs) and to normalize food intake and glucose homeostasis in overfed rats. To this end, we targeted the liver isoform of carnitine palmitoyltransferase-1 (encoded by the CPT1A gene) by infusing either a sequence-specific ribozyme against CPT1A or an isoform-selective inhibitor of CPT1A activity in the third cerebral ventricle or in the mediobasal hypothalamus (MBH). Inhibition of CPT1A activity normalized the hypothalamic levels of LCFA-CoAs and markedly inhibited feeding behavior and hepatic glucose fluxes in overfed rats. Thus central inhibition of lipid oxidation is sufficient to restore hypothalamic lipid sensing as well as glucose and energy homeostasis in this model and may be an effective approach to the treatment of diet-induced obesity and insulin resistance.

MeSH Terms
Animals Carnitine O-Palmitoyltransferase/antagonists & inhibitors,metabolism Energy Metabolism/physiology Glucose/biosynthesis Homeostasis Hyperphagia/metabolism Hypothalamus/metabolism,physiology Lipid Metabolism/physiology Liver/cytology,metabolism Male Models, Biological Oxidation-Reduction Rats Rats, Sprague-Dawley
Chemicals
Carnitine O-Palmitoyltransferase Glucose
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Pocai Alessandro
Department of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, New York, New York, USA.
Lam Tony K T
Obici Silvana
Gutierrez-Juarez Roger
Muse Evan D
Arduini Arduino
Rossetti Luciano
References (48)
48 references, click to expand
  1. Identification of targets of leptin action in rat hypothalamus.
    J Clin Invest. 1996 Sep 1;98(5):1101-6 PMID: 8787671
  2. Central leptin acutely reverses diet-induced hepatic insulin resistance.
    Diabetes. 2005 Nov;54(11):3182-9 PMID: 16249443
  3. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors.
    Science. 2000 Jun 30;288(5475):2379-81 PMID: 10875926
  4. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985.
    J Biol Chem. 2000 Dec 22;275(51):40649-57 PMID: 11018044
  5. Cerulenin mimics effects of leptin on metabolic rate, food intake, and body weight independent of the melanocortin system, but unlike leptin, cerulenin fails to block neuroendocrine effects of fasting.
    Diabetes. 2001 Apr;50(4):733-9 PMID: 11289036
  6. Overfeeding rapidly induces leptin and insulin resistance.
    Diabetes. 2001 Dec;50(12):2786-91 PMID: 11723062
  7. Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides.
    Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):66-71 PMID: 11756683
  8. Central administration of oleic acid inhibits glucose production and food intake.
    Diabetes. 2002 Feb;51(2):271-5 PMID: 11812732
  9. Differential effects of a centrally acting fatty acid synthase inhibitor in lean and obese mice.
    Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1921-5 PMID: 11854492
  10. Block the FAS, lose the fat.
    Nat Med. 2002 Apr;8(4):335-6 PMID: 11927935
  11. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats.
    Nat Neurosci. 2002 Jun;5(6):566-72 PMID: 12021765
  12. C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity.
    Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9498-502 PMID: 12060712
  13. Prevalence and trends in obesity among US adults, 1999-2000.
    JAMA. 2002 Oct 9;288(14):1723-7 PMID: 12365955
  14. Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment.
    Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E867-79 PMID: 12376313
  15. Hypothalamic insulin signaling is required for inhibition of glucose production.
    Nat Med. 2002 Dec;8(12):1376-82 PMID: 12426561
  16. A war on obesity, not the obese.
    Science. 2003 Feb 7;299(5608):856-8 PMID: 12574619
  17. Obesity.
    Clin Med. 2003 Jan-Feb;3(1):23-7 PMID: 12617409
  18. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fa(k)/fa(k)) rats.
    Endocrinology. 2003 May;144(5):2016-24 PMID: 12697710
  19. Assessment of the aversive consequences of acute and chronic administration of the melanocortin agonist, MTII.
    Int J Obes Relat Metab Disord. 2003 May;27(5):550-6 PMID: 12704398
  20. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production.
    Nat Med. 2003 Jun;9(6):756-61 PMID: 12754501
  21. Minireview: nutrient sensing and the regulation of insulin action and energy balance.
    Endocrinology. 2003 Dec;144(12):5172-8 PMID: 12970158
  22. Obesity wars: molecular progress confronts an expanding epidemic.
    Cell. 2004 Jan 23;116(2):337-50 PMID: 14744442
  23. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus.
    Nature. 2004 Apr 1;428(6982):569-74 PMID: 15058305
  24. Long-term effects of a fatty acid synthase inhibitor on obese mice: food intake, hypothalamic neuropeptides, and UCP3.
    Biochem Biophys Res Commun. 2004 Apr 30;317(2):301-8 PMID: 15063757
  25. C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase.
    J Biol Chem. 2004 May 7;279(19):19970-6 PMID: 15028725
  26. Hypothalamic responses to long-chain fatty acids are nutritionally regulated.
    J Biol Chem. 2004 Jul 23;279(30):31139-48 PMID: 15155754
  27. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice.
    Endocrinology. 2004 Nov;145(11):4880-9 PMID: 15271881
  28. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons.
    Nature. 1979 Nov 29;282(5738):503-5 PMID: 116135
  29. Reduction of food intake and body weight by chronic intraventricular insulin infusion.
    Brain Res Bull. 1984 May;12(5):571-5 PMID: 6380652
  30. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.
    J Clin Invest. 2000 Jun;105(12):1827-32 PMID: 10862798
  31. Extraction of tissue long-chain acyl-CoA esters and measurement by reverse-phase high-performance liquid chromatography.
    Anal Biochem. 1985 Oct;150(1):8-12 PMID: 4083485
  32. Determination of short-chain acyl-coenzyme A esters by high-performance liquid chromatography.
    Anal Biochem. 1986 Feb 15;153(1):45-9 PMID: 3963382
  33. Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats.
    Am J Physiol. 1986 Nov;251(5 Pt 1):E576-83 PMID: 3535532
  34. Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats.
    Diabetes. 1991 Nov;40(11):1397-403 PMID: 1936601
  35. Evidence for the involvement of carnitine-dependent long-chain acyltransferases in neuronal triglyceride and phospholipid fatty acid turnover.
    J Neurochem. 1994 Apr;62(4):1530-8 PMID: 8133280
  36. Positional cloning of the mouse obese gene and its human homologue.
    Nature. 1994 Dec 1;372(6505):425-32 PMID: 7984236
  37. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine.
    Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7297-301 PMID: 7638184
  38. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action.
    Nat Med. 1995 Dec;1(12):1311-4 PMID: 7489415
  39. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice.
    Diabetes. 1996 Apr;45(4):531-5 PMID: 8603777
  40. Leptin selectively decreases visceral adiposity and enhances insulin action.
    J Clin Invest. 1997 Dec 15;100(12):3105-10 PMID: 9399957
  41. Deconstructing type 2 diabetes.
    Cell. 1999 Apr 2;97(1):9-12 PMID: 10199397
  42. Diabetes, obesity, and the brain.
    Science. 2005 Jan 21;307(5708):375-9 PMID: 15662002
  43. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis.
    Nat Med. 2005 Mar;11(3):320-7 PMID: 15735652
  44. Reduced anorexic effects of insulin in obesity-prone rats fed a moderate-fat diet.
    Am J Physiol Regul Integr Comp Physiol. 2005 Apr;288(4):R981-6 PMID: 15604298
  45. Hypothalamic K(ATP) channels control hepatic glucose production.
    Nature. 2005 Apr 21;434(7036):1026-31 PMID: 15846348
  46. Molecular and anatomical determinants of central leptin resistance.
    Nat Neurosci. 2005 May;8(5):566-70 PMID: 15856064
  47. A brain-liver circuit regulates glucose homeostasis.
    Cell Metab. 2005 Jan;1(1):53-61 PMID: 16054044
  48. Diet-induced obese mice develop peripheral, but not central, resistance to leptin.
    J Clin Invest. 1997 Feb 1;99(3):385-90 PMID: 9022070
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI26640
Published
2006-04-00
Epub
2006-00-09
Pages
1081-91
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1395479
Subset
IM
Grants
NIDDK NIH HHS · R01 DK045024 · United States
NIA NIH HHS · P01 AG021654 · United States
NIDDK NIH HHS · DK 48321 · United States
NIA NIH HHS · T32 AG023475 · United States
NIDDK NIH HHS · DK 45024 · United States
NIDDK NIH HHS · R01 DK048321 · United States
NIDDK NIH HHS · P30 DK020541 · United States
NIA NIH HHS · AG 21654 · United States
NIDDK NIH HHS · P60 DK020541 · United States
NIDDK NIH HHS · DK 20541 · United States
NIA NIH HHS · T32-AG023475 · United States
NIDDK NIH HHS · R37 DK048321 · United States
External Links
PubMed source DOI: 10.1172/JCI26640 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2