PPARα is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue

Abstract

Adenovirus-induced hyperleptinemia causes rapid disappearance of body fat in normal rats, presumably by up-regulating fatty acid oxidation within white adipocytes. To determine the role of peroxisomal proliferation-activated receptor (PPAR)␣ expression, which was increased during the rapid loss of fat, we infused adenovirus-leptin into PPAR␣ ؊/؊ and PPAR␣ ؉/؉ mice. Despite similar degrees of hyperleptinemia and reduction in food intake, epididymal fat pad weight declined 55% in wild-type but only 6% in PPAR␣ ؊/؊ mice; liver triacylglycerol fell 39% in the wild-type group but was unchanged in PPAR ؊/؊ mice. Carnitine palmitoyl transferase-1 mRNA rose 52% in the wild-type mice but did not increase in PPAR␣ ؊/؊ mice. PPAR␥ coactivator-1␣ rose 3-fold in the fat and 46% in the liver of wild-type mice but was unchanged in PPAR␣ ؊/؊ mice. Although AMP-activated protein kinase could not be implicated in the lipopenic actions of hyperleptinemia, acetyl CoA carboxylase protein was reduced in the liver of wild-type but not in PPAR␣ ؊/؊ mice. Thus, in PPAR␣ ؊/؊ mice, up-regulation of carnitine palmitoyl transferase-1 mRNA in fat, down-regulation of acetyl CoA carboxylase in liver, and up-regulation of PPAR␥ coactivator-1␣ mRNA in both tissues are abolished, as is the reduction in their triacylglycerol content. S ustained hyperleptinemia induced in normal rats by adenovirus transfer of the leptin cDNA results in virtually complete disappearance of body fat within 7 days (1, 2). The loss of fat is unique in its rapidity and magnitude and, remarkably, it is unassociated with any increase in plasma free fatty acid or ketone levels. This surprising fact led to the proposal that the fat-storing white adipocytes had been transformed by hyperleptinemia into fatburning cells, i.e., that fatty acids were being oxidized inside the adipocytes (3). The expression profiles of enzymes of fatty acid metabolism in the disappearing white adipose tissue (WAT) were, in fact, consistent with this idea. The transcription factors and enzymes of lipogenesis in WAT were profoundly reduced, whereas those involved in fatty acid (FA) oxidation, including peroxisome proliferator-activated receptor (PPAR)␣, were higher than normal (2). In addition, the mRNA and protein of uncoupling proteins UCP-1 and -2, not normally expressed in WAT, were increased (4). The mRNA of peroxisome proliferator-activated receptor ␥ coactivator (PGC)-1␣ (5), also not normally expressed in WAT, was up-regulated (6). These radical changes implied that fat-storing white adipocytes had become ''fat-burning'' adipocytes.The prominent increase in the expression of PPAR␣ in WAT (6, 7) suggested that it might be a proximal mediator of leptin action and, by up-regulating its target enzymes of FA oxidation, carnitine palmitoyl transferase (CPT)-1 and acyl CoA oxidase (ACO), play a role in the disappearance of adipocyte fat. In addition, it seemed possible that PPAR␣ might be involved in other changes in the expression profile of the overleptinized rats, such as the upregulation of UCP...

The Transcriptional Coactivator Peroxisome Proliferator–Activated Receptor (PPAR)γ Coactivator-1α and the Nuclear Receptor PPARα Control the Expression of Glycerol Kinase and Metabolism Genes Independently of PPARγ Activation in Human White Adipocytes

“…Besides the well-established systemic effect of PPAR␣ agonists on energy expenditure and fat oxidation, it has recently been suggested that activation of the nuclear receptor in WAT could prevent adipocyte hypertrophy (36). In line with this concept, PPAR␣ is essential for the lipopenic effect of hyperleptinemia on WAT (37). Furthermore, PPAR␣ mediates the action of a ␤ 3 -adrenergic receptor agonist on WAT gene expression and remodeling (21).…”

Bile Acid-regulated Peroxisome Proliferator-activated Receptor-α (PPARα) Activity Underlies Circadian Expression of Intestinal Peptide Absorption Transporter PepT1/Slc15a1

“…This nuclear receptor has critical roles in energy metabolism, hepatic steatosis, inflammation, cardiac pathophysiology, cell cycle regulation, and oncogenesis (31,32). In hepatic cells, the modulatory action of bile acids on PPAR␣-mediated transactivation has been shown to affect the expression of genes, including those involved in lipid homeostasis (24,33).…”

Rapid transformation of white adipocytes into fat-oxidizing machines

“…Because PGC-1␣ is involved in mitochondrial biogenesis (21-23), its increase may have played a role in the abundance of mitochondria in postadipocytes. Indeed, when PGC-1␣ is not increased, as in fat cells of adenovirus-leptin-treated PPAR␣-null mice, the hyperleptinemia fails to induce adipocyte fat loss (12). Because forced expression of PGC-1␣ in human fat cells enhances their oxidation of fatty acids (24), it is quite likely that its increase was responsible for the loss of fat through ''internal combustion.''…”