Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis

Frederic Preitner, Nimesh Mody, Timothy E Graham, Odile D Peroni, Barbara B Kahn

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

The synthetic retinoid Fenretinide (FEN) increases insulin sensitivity in obese rodents and is in early clinical trials for treatment of insulin resistance in obese humans with hepatic steatosis (46). We aimed to determine the physiological mechanisms for the insulin-sensitizing effects of FEN. Wild-type mice were fed a high-fat diet (HFD) with or without FEN from 4-5 wk to 36-37 wk of age (preventive study) or following 22 wk of HF diet-induced obesity (12 wk intervention study). Retinol-binding protein-4 (RBP4) knockout mice were also fed the HFD with or without FEN in a preventive study. FEN had minimal effects on HFD-induced body weight gain but markedly reduced HFD-induced adiposity and hyperleptinemia in both studies. FEN-HFD mice gained epididymal fat but not subcutaneous or visceral fat mass in contrast to HFD mice without FEN. FEN did not have a measurable effect on energy expenditure, food intake, physical activity, or stool lipid content. Glucose infusion rate during hyperinsulinemic-euglycemic clamp was reduced 86% in HFD mice compared with controls and was improved 3.6-fold in FEN-HFD compared with HFD mice. FEN improved insulin action on glucose uptake and glycogen levels in muscle, insulin-stimulated suppression of hepatic glucose production, and suppression of serum FFA levels in HFD mice. Remarkably, FEN also reduced hepatic steatosis. In RBP4 knockout mice, FEN reduced the HFD-induced increase in adiposity and hyperleptinemia. In conclusion, long-term therapy with FEN partially prevents or reverses obesity, insulin resistance, and hepatic steatosis in mice on HFD. The anti-adiposity effects are independent of the RBP4 lowering effect.
Original languageEnglish
Pages (from-to)E1420-E1429
Number of pages10
JournalAmerican Journal of Physiology: Endocrinology and Metabolism
Volume297
Issue number6
Early online date13 Oct 2009
DOIs
Publication statusPublished - 1 Dec 2009

Fingerprint

Fenretinide
High Fat Diet
Insulin Resistance
Obesity
Liver
Retinol-Binding Proteins
Adiposity
Insulin
Glucose
Knockout Mice
Glucose Clamp Technique
Intra-Abdominal Fat
Subcutaneous Fat
Retinoids
Glycogen

Keywords

  • animals
  • body composition
  • body weight
  • calorimetry, indirect
  • cohort studies
  • drug administration schedule
  • eating
  • fatty liver
  • fenretinide
  • glucose clamp technique
  • insulin resistance
  • male
  • mice
  • mice, inbred C57BL
  • mice, knockout
  • obesity
  • retinoids
  • retinol-binding proteins, plasma
  • retinol-binding protein-4
  • type 2 diabetes
  • hyperleptinemia

Cite this

Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. / Preitner, Frederic; Mody, Nimesh; Graham, Timothy E; Peroni, Odile D; Kahn, Barbara B.

In: American Journal of Physiology: Endocrinology and Metabolism, Vol. 297, No. 6, 01.12.2009, p. E1420-E1429.

Research output: Contribution to journalArticle

Preitner, Frederic ; Mody, Nimesh ; Graham, Timothy E ; Peroni, Odile D ; Kahn, Barbara B. / Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. In: American Journal of Physiology: Endocrinology and Metabolism. 2009 ; Vol. 297, No. 6. pp. E1420-E1429.
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T1 - Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis

AU - Preitner, Frederic

AU - Mody, Nimesh

AU - Graham, Timothy E

AU - Peroni, Odile D

AU - Kahn, Barbara B

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N2 - The synthetic retinoid Fenretinide (FEN) increases insulin sensitivity in obese rodents and is in early clinical trials for treatment of insulin resistance in obese humans with hepatic steatosis (46). We aimed to determine the physiological mechanisms for the insulin-sensitizing effects of FEN. Wild-type mice were fed a high-fat diet (HFD) with or without FEN from 4-5 wk to 36-37 wk of age (preventive study) or following 22 wk of HF diet-induced obesity (12 wk intervention study). Retinol-binding protein-4 (RBP4) knockout mice were also fed the HFD with or without FEN in a preventive study. FEN had minimal effects on HFD-induced body weight gain but markedly reduced HFD-induced adiposity and hyperleptinemia in both studies. FEN-HFD mice gained epididymal fat but not subcutaneous or visceral fat mass in contrast to HFD mice without FEN. FEN did not have a measurable effect on energy expenditure, food intake, physical activity, or stool lipid content. Glucose infusion rate during hyperinsulinemic-euglycemic clamp was reduced 86% in HFD mice compared with controls and was improved 3.6-fold in FEN-HFD compared with HFD mice. FEN improved insulin action on glucose uptake and glycogen levels in muscle, insulin-stimulated suppression of hepatic glucose production, and suppression of serum FFA levels in HFD mice. Remarkably, FEN also reduced hepatic steatosis. In RBP4 knockout mice, FEN reduced the HFD-induced increase in adiposity and hyperleptinemia. In conclusion, long-term therapy with FEN partially prevents or reverses obesity, insulin resistance, and hepatic steatosis in mice on HFD. The anti-adiposity effects are independent of the RBP4 lowering effect.

AB - The synthetic retinoid Fenretinide (FEN) increases insulin sensitivity in obese rodents and is in early clinical trials for treatment of insulin resistance in obese humans with hepatic steatosis (46). We aimed to determine the physiological mechanisms for the insulin-sensitizing effects of FEN. Wild-type mice were fed a high-fat diet (HFD) with or without FEN from 4-5 wk to 36-37 wk of age (preventive study) or following 22 wk of HF diet-induced obesity (12 wk intervention study). Retinol-binding protein-4 (RBP4) knockout mice were also fed the HFD with or without FEN in a preventive study. FEN had minimal effects on HFD-induced body weight gain but markedly reduced HFD-induced adiposity and hyperleptinemia in both studies. FEN-HFD mice gained epididymal fat but not subcutaneous or visceral fat mass in contrast to HFD mice without FEN. FEN did not have a measurable effect on energy expenditure, food intake, physical activity, or stool lipid content. Glucose infusion rate during hyperinsulinemic-euglycemic clamp was reduced 86% in HFD mice compared with controls and was improved 3.6-fold in FEN-HFD compared with HFD mice. FEN improved insulin action on glucose uptake and glycogen levels in muscle, insulin-stimulated suppression of hepatic glucose production, and suppression of serum FFA levels in HFD mice. Remarkably, FEN also reduced hepatic steatosis. In RBP4 knockout mice, FEN reduced the HFD-induced increase in adiposity and hyperleptinemia. In conclusion, long-term therapy with FEN partially prevents or reverses obesity, insulin resistance, and hepatic steatosis in mice on HFD. The anti-adiposity effects are independent of the RBP4 lowering effect.

KW - animals

KW - body composition

KW - body weight

KW - calorimetry, indirect

KW - cohort studies

KW - drug administration schedule

KW - eating

KW - fatty liver

KW - fenretinide

KW - glucose clamp technique

KW - insulin resistance

KW - male

KW - mice

KW - mice, inbred C57BL

KW - mice, knockout

KW - obesity

KW - retinoids

KW - retinol-binding proteins, plasma

KW - retinol-binding protein-4

KW - type 2 diabetes

KW - hyperleptinemia

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DO - 10.1152/ajpendo.00362.2009

M3 - Article

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VL - 297

SP - E1420-E1429

JO - American Journal of Physiology: Endocrinology and Metabolism

JF - American Journal of Physiology: Endocrinology and Metabolism

SN - 0193-1849

IS - 6

ER -