Peroxisome Proliferator-activated Receptor α-Isoform Deficiency Leads to Progressive Dyslipidemia with Sexually Dimorphic Obesity and Steatosis

Abstract

The ␣-isoform of the peroxisome proliferator-activated receptor (PPAR␣) is a nuclear transcription factor activated by structurally diverse chemicals referred to as peroxisome proliferators. Activators can be endogenous molecules (fatty acids/steroids) or xenobiotics (fibrate lipid-lowering drugs). Upon pharmacological activation, PPAR␣ modulates target genes encoding lipid metabolism enzymes, lipid transporters, or apolipoproteins, suggesting a role in lipid homeostasis. Transgenic mice deficient in PPAR␣ were shown to lack hepatic peroxisomal proliferation and have an impaired expression and induction of several hepatic target genes. Young adult males show hypercholesterolemia but normal triglycerides. Using a long term experimental set up, we identified these mice as a model of monogenic, spontaneous, late onset obesity with stable caloric intake and a marked sexual dimorphism. Serum triglycerides, elevated in aged animals, are higher in females that develop a more pronounced obesity than males. The latter show a marked and original centrilobular-restricted steatosis and a delayed occurrence of obesity. Fat cells from their liver express substantial levels of PPAR␥2 transcripts when compared with lean cells. These studies demonstrate, in rodents, the involvement of PPAR␣ nuclear receptor in lipid homeostasis, with a sexually dimorphic control of circulating lipids, fat storage, and obesity. Characterization of this pathological link may help to delineate new molecular targets for therapeutic intervention and could lead to new insights into the etiology and heritability of mammalian obesity.Obesity, an increasing health problem in wealthy societies, has been causatively linked to hyperlipidemia, diabetes, hypertension, and atherosclerosis. Adipose cell hypertrophy and hyperplasia occur as the ultimate consequence of a disequilibrium in energy balance and exert adverse effects on longevity (1, 2). Several causal genetic determinants responsible for spontaneous monogenic obesity in mice (ob, db, tub, A r , and fat genes) have been identified (reviewed in Ref. 3). In humans, a limited number of obese syndromes have been related to single gene disorders (e.g. Ahlstrom, Bardet Biedl, Cohen, Prader Willi). Recently, two mutations, affecting the leptin signal transduction pathway and leading to human early onset morbid obesity, have been characterized. They affect the ob gene (4), encoding leptin, and the leptin receptor gene (5), respectively. A mutation in the human prohormone convertase 1 gene, leading to childhood obesity, has been documented (6), and tissue-specific attenuation of the prohormone convertase 2 gene has been reported in two patients with Prader-Willi syndrome (7). Proconvertases act, proximally to carboxypeptidase E, in the pathway of post-translational processing of prohormones and neuropeptides, therefore associating this syndrome with the fat/fat murine phenotype. Prevalence of these mutations in the human obese population was reported as being rather limited (4, 5), and human counterparts ...

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: The HyperGEN Study

“…Interactions with sex have been reported previously from studies of Finnish 54 and Norwegian 55 twins, from a segregation analysis of the Québec Family Study, 56 and from studies of inbred rat strains that have found sex-specific QTLs for obesity. 57 Sexual dimorphism has also been observed in such characteristics as leptin concentration and ob gene expression; 58 expression of hormone-sensitive lipase and lipoprotein lipase in subcutaneous abdominal fat in response to weight loss; 59 fat deposition in PPAR-a knockout mice; 60 the effect of variants in the leptin receptor, 61 and in the leptin gene itself. 62 While it is important to determine whether sex-specific QTLs for adiposity replicate in other studies, our results suggest that sex may have important environmental influences and that our ability to identify relevant genes may be improved by incorporating such effects into our linkage models.…”

PPARs and adipocyte function

“…However, these animals display spontaneous, sexually dimorphic, late onset obesity (despite stable caloric intake) which is associated with adipocyte hypertrophy [91]. Furthermore, they are prone to diet-induced obesity which paradoxically is associated with enhanced insulin sensitivity [92].…”

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

“…Male PPAR-null mice on a C57BL/6J genetic background [36,37], and aged-matched wildtype counterparts (Charles River, Les Oncins, France; 4 weeks acclimatization) were housed in polycarbonate cages at 22 + 2°C on a 12 hour light/dark cycle and allowed free access to water and food. In vivo studies were conducted under European Union Guidelines for the use and care of laboratory animals and were approved by an independent ethics committee.…”