Abstract
Perlecan (HSPG2), a heparan sulfate proteoglycan, is a component of basement membranes and participates in a variety of biological activities. Here, we show physiological roles of perlecan in both obesity and the onset of metabolic syndrome. The perinatal lethality-rescued perlecan knockout (Hspg2−/−-Tg) mice showed a smaller mass and cell size of white adipose tissues than control (WT-Tg) mice. Abnormal lipid deposition, such as fatty liver, was not detected in the Hspg2−/−-Tg mice, and those mice also consumed more fat as an energy source, likely due to their activated fatty acid oxidation. In addition, the Hspg2−/−-Tg mice demonstrated increased insulin sensitivity. Molecular analysis revealed the significantly relatively increased amount of the muscle fiber type IIA (X) isoform and a larger quantity of mitochondria in the skeletal muscle of Hspg2−/−-Tg mice. Furthermore, the perlecan-deficient skeletal muscle also had elevated levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) protein. PGC1α expression is activated by exercise, and induces mitochondrial biosynthesis. Thus, perlecan may act as a mechano-regulator of catabolism of both lipids and glucose by shifting the muscle fiber composition to oxidative fibers. Our data suggest that downregulation of perlecan is a promising strategy to control metabolic syndrome.
Highlights
In recent years, human lifestyles have been largely changed, and metabolic syndrome is threatening human health by enhancing the risks of cardiovascular disease and diabetes mellitus[1,2,3]
We investigated the physiological relationships between perlecan and obesity using Hspg2−/−-Tg mice
We examined cholesterol concentrations in four major lipoproteins: chylomicrons (CM), very low density lipoproteins (VLDL), low density lipoproteins (LDL), and high density lipoproteins (HDL)
Summary
Human lifestyles have been largely changed, and metabolic syndrome is threatening human health by enhancing the risks of cardiovascular disease and diabetes mellitus[1,2,3]. Adipose tissue and skeletal muscle are representative organs for the regulation of systemic metabolic dynamics, and both show dynamic changes in morphology and functions in response to environmental stimuli, such as diet and exercise conditions. The development of metabolic syndrome is associated with dynamic remodeling of both adipose tissue and adipocytes[7,8]. Types I, IIA, IIX, and IIB are distinguished by the maximum speed of contraction and the attributed energy metabolism[9,10]. The maximum speed of muscle contraction varies among the type II fibers with IIB as the fastest and IIX faster than IIA11,12. The dynamics of ECMs are associated with increased insulin resistance in skeletal muscle[18], and with differentiation and remodeling of adipocytes in response to energy balance[19,20]. Perlecan has been implicated in the regulation of the lipid dynamics of adipose tissue
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