Induction of uncoupling protein in brown adipose tissue: Synergy between norepinephrine and pioglitazone, an insulin-sensitizing agent

doi:10.1016/0006-2952(96)00345-0

Biochemical Pharmacology

Volume 52, Issue 5, 13 September 1996, Pages 693-701

https://doi.org/10.1016/0006-2952(96)00345-0 Get rights and content

Abstract

Insulin resistance and obesity in rodent models of non-insulin-dependent diabetes mellitus have been correlated with ablated or defective brown adipose tissue (BAT) function. The mitochondrial uncoupling protein (UCP) allows BAT to perform its unique role in facultative energy expenditure. In this study, we observed an increase in both BAT mass and the expression of UCP mRNA in BAT from obese diabetic mice and their lean littermates following treatment with the thiazolidinedione pioglitazone, a novel insulin-sensitizing agent. Thus, we wanted to ascertain if pioglitazone directly induces BAT differentiation. We found that treatment for 48 hr with pioglitazone caused a 32-fold increase in UCP mRNA, whereas a 7-hr treatment with norepinephrine caused a 24-fold increase in expression. Cells treated with pioglitazone for 48 hr, with norepinephrine added during the last 7 hr, demonstrated a 59-fold increase in UCP mRNA. However, simultaneous treatment with pioglitazone and repeated treatment norepinephrine for 48 hr yielded a greater than 200-fold increase in UCP mRNA. Examination of UCP protein levels demonstrated a similar time-dependent increase with pioglitazone and/or norepinephrine treatment, as well as a synergistic increase with concurrent pioglitazone and norepinephrine treatment. This study shows that pioglitazone exerts a direct effect on BAT cells in vitro by increasing UCP mRNA and protein levels, and that it also synergizes with norepinephrine perhaps by inducing and stabilizing UCP mRNA and/or preventing proteolysis of UCP protein.

References (36)

J Himms-Hagen
Brown adipose tissue thermogenesis and obesity
Prog Lipid Res
(1989)
D Ricquier et al.
Expression of uncoupling protein mRNA in thermogenic or weakly thermogenic brown adipose tissue
J Biol Chem
(1986)
F Bouillaud et al.
Increased level of mRNA for the uncoupling protein in brown adipose tissue in rats during thermogenesis induced by cold exposure or norepinephrine infusion
J Biol Chem
(1984)
AC Bianco et al.
Triiodothyronine amplifies norepinephrine stimulation of uncoupling protein gene transcription by a mechanism not requiring protein synthesis
J Biol Chem
(1988)
D Herron et al.
Norepinephrine-induced synthesis of the uncoupling protein thermogenin (UCP) and its mitochondrial targeting in brown adipocytes differentiated in culture
FEBS Lett
(1990)
S Rehnmark et al.
α- and β-Adrenergic induction of the expression of the uncoupling protein thermogenin in brown adipocytes differentiated in culture
J Biol Chem
(1990)
NJ Rothwell et al.
Effects of ciglitazone on energy balance, thermogenesis and brown fat activity in the rat
Mol Cell Endocrinol
(1987)
SW Mercer et al.
Effects of ciglitazone on insulin resistance and thermogenic responsiveness to acute cold in brown adipose tissue of genetically obese (ob/ob) mice
FEBS Lett
(1986)
M Néchad et al.
Development of brown fat cells in monolayer culture: Morphological and biochemical distinction from white fat cells in culture
Exp Cell Res
(1983)
PK Smith et al.
Measurement of protein using bicinchoninic acid
Anal Biochem
(1985)

B Cannon et al.

Exclusive occurrence of thermogenin antigen in brown adipose tissue

FEBS Lett

(1982)

JM Lehmann et al.

An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferatoractivated receptor γ (PPARγ)

J Biol Chem

(1995)

RE Smith et al.

Brown fat and thermogenesis

Physiol Rev

(1969)

NJ Rothwell et al.

A role for brown adipose tissue in diet-induced thermogenesis

Nature

(1979)

BB Lowell et al.

Development of obesity in transgenic mice after genetic ablation of brown adipose tissue

Nature

(1993)

SW Mercer et al.

The development of insulin resistance in brown adipose tissue may impair the acute coldinduced activation of thermogenesis in genetically obese (ob/ ob) mice

Biosci Rep

(1984)

DG Nicholls et al.

Thermogenic mechanisms in brown fat

Physiol Rev

(1984)

RF Kletzien et al.

Enhancement of adipocyte differentiation by an insulin-sensitizing agent

Mol Pharmacol

(1992)

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Brown adipose tissue (BAT) is a potential target to treat obesity and diabetes, dissipating energy as heat. Type 2 diabetes (T2D) has been associated with obesogenic diets; however, T2D was also reported in lean individuals to be associated with genetic factors. We aimed to investigate the differences between obese and lean models of insulin resistance (IR) and elucidate the mechanism associated with BAT metabolism and dysfunction in different IR animal models: a genetic model (lean GK rats) and obese models (diet-induced obese Wistar rats) at 8 weeks of age fed a high-carbohydrate (HC), high-fat (HF) diet, or high-fat and high-sugar (HFHS) diet for 8 weeks. At 15 weeks of age, BAT glucose uptake was evaluated by 18F-FDG PET under basal (saline administration) or stimulated condition (CL316,243, a selective β3-AR agonist). After CL316, 243 administrations, GK animals showed decreased glucose uptake compared to HC animals. At 16 weeks of age, the animals were euthanized, and the interscapular BAT was dissected for analysis. Histological analyses showed lower cell density in GK rats and higher adipocyte area compared to all groups, followed by HFHS and HF compared to HC. HFHS showed a decreased batokine FGF21 protein level compared to all groups. However, GK animals showed increased expression of genes involved in fatty acid oxidation (CPT1 and CPT2), BAT metabolism (Sirt1 and Pgc1-α), and obesogenic genes (leptin and PAI-1) but decreased gene expression of glucose transporter 1 (GLUT-1) compared to other groups. Our data suggest impaired BAT function in obese Wistar and GK rats, with evidence of a whitening process in these animals
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Citation Excerpt :
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Although, the reason for the unexpected UCP1 expression in WAT in hPXR mice requires further investigation, it is well established that leptin regulates UCP1 gene [71]. Furthermore, the PPARγ agonist pioglitazone, essential fatty acids and retinoids have been reported to activate UCP1 gene expression [72–75]. We have recently shown that the basal serum leptin levels are higher in both male PXR-KO and hPXR mice than in WT mice [45].
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Research paperInduction of uncoupling protein in brown adipose tissue: Synergy between norepinephrine and pioglitazone, an insulin-sensitizing agent

Abstract

Prog Lipid Res

J Biol Chem

J Biol Chem

J Biol Chem

FEBS Lett

J Biol Chem

Mol Cell Endocrinol

FEBS Lett

Exp Cell Res

Anal Biochem

FEBS Lett

J Biol Chem

Brown fat and thermogenesis

Physiol Rev

A role for brown adipose tissue in diet-induced thermogenesis

Nature

Development of obesity in transgenic mice after genetic ablation of brown adipose tissue

Nature

The development of insulin resistance in brown adipose tissue may impair the acute coldinduced activation of thermogenesis in genetically obese (ob/ ob) mice

Biosci Rep

Thermogenic mechanisms in brown fat

Physiol Rev

Enhancement of adipocyte differentiation by an insulin-sensitizing agent

Mol Pharmacol

Research paper
Induction of uncoupling protein in brown adipose tissue: Synergy between norepinephrine and pioglitazone, an insulin-sensitizing agent