Modulation of adipose tissue lipolysis and body weight by high-density lipoproteins in mice

Abstract

Background:Obesity is associated with reduced levels of circulating high-density lipoproteins (HDLs) and its major protein, apolipoprotein (apo) A-I. As a result of the role of HDL and apoA-I in cellular lipid transport, low HDL and apoA-I may contribute directly to establishing or maintaining the obese condition.Methods:To test this, male C57BL/6 wild-type (WT), apoA-I deficient (apoA-I−/−) and apoA-I transgenic (apoA-Itg/tg) mice were fed obesogenic diets (ODs) and monitored for several clinical parameters. We also performed cell culture studies.Results:ApoA-I−/− mice gained significantly more body weight and body fat than WT mice over 20 weeks despite their reduced food intake. During a caloric restriction regime imposed on OD-fed mice, apoA-I deficiency significantly inhibited the loss of body fat as compared with WT mice. Reduced body fat loss with caloric restriction in apoA-I−/− mice was associated with blunted stimulated adipose tissue lipolysis as verified by decreased levels of phosphorylated hormone-sensitive lipase (p-HSL) and lipolytic enzyme mRNA. In contrast to apoA-I−/− mice, apoA-Itg/tg mice gained relatively less weight than WT mice, consistent with other reports. ApoA-Itg/tg mice showed increased adipose tissue lipolysis, verified by increased levels of p-HSL and lipolytic enzyme mRNA. In cell culture studies, HDL and apoA-I specifically increased catecholamine-induced lipolysis possibly through modulating the adipocyte plasma membrane cholesterol content.Conclusions:Thus, apoA-I and HDL contribute to modulating body fat content by controlling the extent of lipolysis. ApoA-I and HDL are key components of lipid metabolism in adipose tissue and constitute new therapeutic targets in obesity.

ApoA-I Milano stimulates lipolysis in adipose cells independently of cAMP/PKA activation

“…Previous studies have described a balance between lipolysis and cholesterol effl ux in adipose cells, where ␤ -adrenergic stimulation of lipolysis in 3T3-L1 adipose cells increased cholesterol effl ux to HDL ( 20,21 ). However, in the latter study, presence of HDL did not itself initiate effl ux of cholesterol from adipose cells.…”

“…Rather, lipolysis has been shown to induce cholesterol effl ux ( 20,21 ). In addition, the cellular effects of the Milano variant have been poorly investigated.…”

“…In contrast, Sviridov et al ( 19 ) suggested that ApoA-I regulates both caveolin-1 expression and intracellular cholesterol traffi cking to caveolae. Of interest, evidence suggests that ␤ -adrenergic stimulated lipolysis increases cholesterol effl ux, emphasizing a balance between triglyceride and cholesterol storage ( 20,21 ).…”

ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction

“…WT mice fed the HFD have been repeatedly shown to gain body weight and fat, accompanied by systemic and adipose tissue infl ammation ( 11,14,15,43,46,51,58 ). What is not known is whether alterations in myeloidderived Abcg1 Ϫ / Ϫ worsen obesity or alter the course of body weight and fat loss during caloric restriction.…”

“…mRNA levels of mouse Nos2 (nitric oxide synthase 2) ( 50 ), Chil3 (chitinase-like 3), Il6, Arg1 (arginase), Abca1, Abcg1, Acat, MCP1, and L32 were measured by real-time RT-PCR using the 7500 realtime PCR System (Applied Biosystems, Foster City, CA) and SybrGreen Master Mix (Bioline USA Inc., Tauton, MA). PCR reactions were performed in duplicate, and the data were analyzed with the ddCt method as previously described ( 51 ). After normalization to internal control L32, the results for each target gene were expressed as fold change from WT control.…”