Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation

Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation

^*Gifford Laboratories, Center for Diabetes Research, Departments of Internal Medicine and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75235; and ^†Department of Veterans Affairs Medical Center, Dallas, TX 75216

Abstract

We have studied mechanisms by which leptin overexpression, which reduces body weight via anorexic and thermogenic actions, induces triglyceride depletion in adipocytes and nonadipocytes. Here we show that leptin alters in pancreatic islets the mRNA of the genes encoding enzymes of free fatty acid metabolism and uncoupling protein-2 (UCP-2). In animals infused with a recombinant adenovirus containing the leptin cDNA, the levels of mRNAs encoding enzymes of mitochondrial and peroxisomal oxidation rose 2- to 3-fold, whereas mRNA encoding an enzyme of esterification declined in islets from hyperleptinemic rats. Islet UCP-2 mRNA rose 6-fold. All in vivo changes occurred in vitro in normal islets cultured with recombinant leptin, indicating direct extraneural effects. Leptin overexpression increased UCP-2 mRNA by more than 10-fold in epididymal, retroperitoneal, and subcutaneous fat tissue of normal, but not of leptin–receptor-defective obese rats. By directly regulating the expression of enzymes of free fatty acid metabolism and of UCP-2, leptin controls intracellular triglyceride content of certain nonadipocytes, as well as adipocytes.

Footnotes

↵ ‡ To whom reprint requests should be addressed at: Center for Diabetes Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-8854.
Roger H. Unger
ABBREVIATIONS:

TG,

triglyceride;

FFA,

free fatty acid(s);

ACC,

acetyl-CoA carboxylase;

RT,

reverse transcriptase;

CPT-I,

carnitine palmitoyltransferase;

ACO,

acyl-CoA oxidase;

GPAT,

glycerol-3-phosphate acyltransferase;

UCP-1 and -2,

uncoupling proteins 1 and 2;

ZDF,

Zucker diabetic fatty;

β-gal,

β-galactosidase;

CMV,

cytomegalovirus