Metabolic and cellular plasticity in white adipose tissue II: role of peroxisome proliferator-activated receptor-α

Abstract

Chronic activation of adipocyte beta-adrenergic receptors induces remodeling of white adipose tissue (WAT) that includes a transient inflammatory response followed by mitochondrial biogenesis, induction of fatty acid oxidation genes, and elevation of tissue oxidative metabolism. Gene profiling experiments of WAT during remodeling induced by the beta(3)-adrenergic receptor agonist CL-316,243 (CL) suggested that peroxisome proliferator-activated receptor-alpha (Ppara), which is upregulated by CL, might be an important transcriptional regulator of that process. Histological, physiological, and molecular analysis of CL-induced remodeling in wild-type mice and mice lacking Ppara demonstrated that Ppara was important for inducing adipocyte mitochondrial biogenesis and upregulating genes involved in fatty acid oxidation. Furthermore, Ppara-deficient mice exhibited sustained WAT inflammation during CL treatment, indicating that upregulation of Ppara limits proinflammatory signaling during chronic lipolytic activation. Together, these data support the hypothesis that WAT remodeling is an adaptive response to excessive fatty acid mobilization whereby Ppara and its downstream targets elevate fatty acid catabolism and suppress proinflammatory signaling.

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

“…4C). As previously reported, the WAT expression of GyK was higher in PPAR␣ Ϫ/Ϫ mice than in wild-type mice (21). PPAR␣ activates GyK gene transcription.…”

“…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). These data on mouse WAT shall however be interpreted with caution because important species differences exist between mouse and human white fat cell metabolism (38).…”

Lipolytic Products Activate Peroxisome Proliferator-activated Receptor (PPAR) α and δ in Brown Adipocytes to Match Fatty Acid Oxidation with Supply

“…mRNA knockdown of PPAR␣ was detected with primers 5Ј-AGGCTGTAAGGGCTTCTTTC-3Ј (forward) and 5Ј-CGAATTGCATTGTGTGACAT-3Ј (reverse) and knockdown of PPAR␦ with 5Ј-GACAATCCGCATGAAG-CTC-3Ј (forward) and 5Ј-GGATAGCGTTGTGCGACAT-3Ј(reverse). All other cDNAs were amplified using primers described previously (11,14,15).…”

“…In contrast, chronic activation of ␤-ARs in WAT produces a catabolic remodeling marked by the appearance of multilocular adipocytes and increased in situ fat oxidation, thereby resembling a BAT-like phenotype (14). This "browning" of white fat is delayed in mice lacking HSL (11) and in mice lacking the nuclear receptor PPAR␣, suggesting that lipolysis might signal via PPARs (15). Recent evidence has also implicated the other major lipase of BAT, ATGL, in regulating the expression of catabolic genes.…”

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

“…Pparg, which is required for adipose tissue formation, has emerged as a transcriptional regulator of metabolism and plays an important role in diabetes and obesity [5]. Ppara is centrally involved in mitochondrial biogenesis and fatty acid oxidation [6]. Increased production of Ppargc1a, a key regulator of mitochondrial biogenesis, may be involved in obesity and the pre-diabetic state in skeletal muscle [7].…”