Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo

Sigal Fishman, Radhika H. Muzumdar, Gil Atzmon, Xiaohui Ma, Xiaoman Yang, Francine H. Einstein, Nir Barzilai

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Impairment of both insulin and leptin action has been implicated in the pathogenesis of nonalcoholic fatty liver disease. By assessing hepatic triglyceride (TG) stores in response to modulation of leptin action (by leptin infusion), we attempted to determine whether leptin has the major role in hepatic TG accumulation. TG were markedly decreased (by 63%, P<0.05) in young animals treated with leptin. However, this was also associated with improvement in hepatic insulin action (2-fold decrease in HGP during clamp, P<0.05). These effects on hepatic TG stores and insulin action were abolished in old rats who demonstrate leptin resistance. Since these experiments could not discern the role of leptin from the role of hepatic insulin action on hepatic TG stores, we further examined the effect of improvement of hepatic insulin action by visceral fat removal (VF-). Enhancement of hepatic insulin action in old VF-rats was associated with reduced hepatic TG stores (by 64% P<0.01). Because this manipulation may have induced an improvement in leptin action as well, we studied VF removal in a genetically leptin-resistant model (Zucker Diabetic Fatty rats, ZDF). Only in this mode was exclusive improvement of hepatic insulin action by VF removal not associated with reduced hepatic TG stores, suggesting that improved hepatic insulin action is not necessary for modulation of hepatic TG stores. By dissociating action of leptin from that of insulin, we suggest that the failure of leptin action is the major physiological mechanism for hepatic steatosis.

Original languageEnglish (US)
Pages (from-to)53-60
Number of pages8
JournalFASEB Journal
Volume21
Issue number1
DOIs
StatePublished - Jan 2007

Fingerprint

Leptin
leptin
Triglycerides
triacylglycerols
liver
Insulin
Liver
insulin
Rats
visceral fat
fatty liver
Intra-Abdominal Fat
Fats
Modulation
rats
Clamping devices
young animals
Animals
pathogenesis

Keywords

  • Hepatic insulin action
  • Metabolic syndrome
  • Steatosis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo. / Fishman, Sigal; Muzumdar, Radhika H.; Atzmon, Gil; Ma, Xiaohui; Yang, Xiaoman; Einstein, Francine H.; Barzilai, Nir.

In: FASEB Journal, Vol. 21, No. 1, 01.2007, p. 53-60.

Research output: Contribution to journalArticle

Fishman, Sigal ; Muzumdar, Radhika H. ; Atzmon, Gil ; Ma, Xiaohui ; Yang, Xiaoman ; Einstein, Francine H. ; Barzilai, Nir. / Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo. In: FASEB Journal. 2007 ; Vol. 21, No. 1. pp. 53-60.
@article{cb30bb9d2bf24c4daa69f3f382b5e02b,
title = "Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo",
abstract = "Impairment of both insulin and leptin action has been implicated in the pathogenesis of nonalcoholic fatty liver disease. By assessing hepatic triglyceride (TG) stores in response to modulation of leptin action (by leptin infusion), we attempted to determine whether leptin has the major role in hepatic TG accumulation. TG were markedly decreased (by 63{\%}, P<0.05) in young animals treated with leptin. However, this was also associated with improvement in hepatic insulin action (2-fold decrease in HGP during clamp, P<0.05). These effects on hepatic TG stores and insulin action were abolished in old rats who demonstrate leptin resistance. Since these experiments could not discern the role of leptin from the role of hepatic insulin action on hepatic TG stores, we further examined the effect of improvement of hepatic insulin action by visceral fat removal (VF-). Enhancement of hepatic insulin action in old VF-rats was associated with reduced hepatic TG stores (by 64{\%} P<0.01). Because this manipulation may have induced an improvement in leptin action as well, we studied VF removal in a genetically leptin-resistant model (Zucker Diabetic Fatty rats, ZDF). Only in this mode was exclusive improvement of hepatic insulin action by VF removal not associated with reduced hepatic TG stores, suggesting that improved hepatic insulin action is not necessary for modulation of hepatic TG stores. By dissociating action of leptin from that of insulin, we suggest that the failure of leptin action is the major physiological mechanism for hepatic steatosis.",
keywords = "Hepatic insulin action, Metabolic syndrome, Steatosis",
author = "Sigal Fishman and Muzumdar, {Radhika H.} and Gil Atzmon and Xiaohui Ma and Xiaoman Yang and Einstein, {Francine H.} and Nir Barzilai",
year = "2007",
month = "1",
doi = "10.1096/fj.06-6557com",
language = "English (US)",
volume = "21",
pages = "53--60",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "1",

}

TY - JOUR

T1 - Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo

AU - Fishman, Sigal

AU - Muzumdar, Radhika H.

AU - Atzmon, Gil

AU - Ma, Xiaohui

AU - Yang, Xiaoman

AU - Einstein, Francine H.

AU - Barzilai, Nir

PY - 2007/1

Y1 - 2007/1

N2 - Impairment of both insulin and leptin action has been implicated in the pathogenesis of nonalcoholic fatty liver disease. By assessing hepatic triglyceride (TG) stores in response to modulation of leptin action (by leptin infusion), we attempted to determine whether leptin has the major role in hepatic TG accumulation. TG were markedly decreased (by 63%, P<0.05) in young animals treated with leptin. However, this was also associated with improvement in hepatic insulin action (2-fold decrease in HGP during clamp, P<0.05). These effects on hepatic TG stores and insulin action were abolished in old rats who demonstrate leptin resistance. Since these experiments could not discern the role of leptin from the role of hepatic insulin action on hepatic TG stores, we further examined the effect of improvement of hepatic insulin action by visceral fat removal (VF-). Enhancement of hepatic insulin action in old VF-rats was associated with reduced hepatic TG stores (by 64% P<0.01). Because this manipulation may have induced an improvement in leptin action as well, we studied VF removal in a genetically leptin-resistant model (Zucker Diabetic Fatty rats, ZDF). Only in this mode was exclusive improvement of hepatic insulin action by VF removal not associated with reduced hepatic TG stores, suggesting that improved hepatic insulin action is not necessary for modulation of hepatic TG stores. By dissociating action of leptin from that of insulin, we suggest that the failure of leptin action is the major physiological mechanism for hepatic steatosis.

AB - Impairment of both insulin and leptin action has been implicated in the pathogenesis of nonalcoholic fatty liver disease. By assessing hepatic triglyceride (TG) stores in response to modulation of leptin action (by leptin infusion), we attempted to determine whether leptin has the major role in hepatic TG accumulation. TG were markedly decreased (by 63%, P<0.05) in young animals treated with leptin. However, this was also associated with improvement in hepatic insulin action (2-fold decrease in HGP during clamp, P<0.05). These effects on hepatic TG stores and insulin action were abolished in old rats who demonstrate leptin resistance. Since these experiments could not discern the role of leptin from the role of hepatic insulin action on hepatic TG stores, we further examined the effect of improvement of hepatic insulin action by visceral fat removal (VF-). Enhancement of hepatic insulin action in old VF-rats was associated with reduced hepatic TG stores (by 64% P<0.01). Because this manipulation may have induced an improvement in leptin action as well, we studied VF removal in a genetically leptin-resistant model (Zucker Diabetic Fatty rats, ZDF). Only in this mode was exclusive improvement of hepatic insulin action by VF removal not associated with reduced hepatic TG stores, suggesting that improved hepatic insulin action is not necessary for modulation of hepatic TG stores. By dissociating action of leptin from that of insulin, we suggest that the failure of leptin action is the major physiological mechanism for hepatic steatosis.

KW - Hepatic insulin action

KW - Metabolic syndrome

KW - Steatosis

UR - http://www.scopus.com/inward/record.url?scp=33846105545&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846105545&partnerID=8YFLogxK

U2 - 10.1096/fj.06-6557com

DO - 10.1096/fj.06-6557com

M3 - Article

C2 - 17099068

AN - SCOPUS:33846105545

VL - 21

SP - 53

EP - 60

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 1

ER -