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1
* Gifford Laboratories, Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; and
VA North Texas Health Care System, Dallas, Texas 75216, USA
1Correspondence: Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-8854, USA. E-Mail: Runger{at}mednet.Swmed.edu
Leptin resistance has been implicated in the pathogenesis of
obesity-related complications involving abnormalities of lipid
metabolism that resemble those of old age. To determine whether
development of leptin resistance in advancing age might account for
such abnormalities, we compared the effects of hyperleptinemia (>40
ng/ml) induced in 2-month-old and 18-month-old lean wild-type (+/+)
Zucker diabetic fatty rats by adenovirus gene transfer. The decline in
food intake, body weight, and body fat in old rats was only 25%, 50%,
and 16%, respectively, of the young rats. Whereas in young rats plasma
free fatty acids fell 44% and triacylglycerol (TG) 94%, neither
changed in the rats. In hyperleptinemic young rats, adipocyte
expression of preadipocyte factor 1 increased dramatically and leptin
mRNA virtually disappeared; there was increased expression of acyl CoA
oxidase, carnitine palmitoyl transferase 1, and their transcription
factor peroxisome proliferator-activated receptor 
, accounting for
the reduction in body fat. These hyperleptinemia-induced changes were
profoundly reduced in the old rats. On a high-fat diet, old rats
consumed 28% more calories than the young and gained 1.5x as much
fat, despite greater endogenous hyperleptinemia. Expression of a
candidate leptin resistance factor, suppressor of cytokine signaling 3
(SOCS-3), was compared in the hypothalamus and white adipocytes of
young and old rats before and after induction of hyperleptinemia;
hypothalamic SOCS-3 mRNA was 
3x higher in old rats before, whereas
it was 3x higher in WAT after, hyperleptinemia. We conclude that the
anorexic and antilipopenic actions of leptin decline with age, possibly
through increased SOCS-3 expression, and that this could account for
the associated abnormalities in lipid metabolism of the elderly.—Wang,
Z.-W., Pan, W.-T., Lee, Y., Kakuma, T., Zhou, Y.-T., Unger, R. H.
The role of leptin resistance in the lipid abnormalities of aging.
Key Words: high-fat diet • hyperleptinemia • SOCS-3 • fatty acids • hypothalamus • lipotoxicity
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