Conjugated linoleic acid supplementation reduces adipose tissue by apoptosis and develops lipodystrophy in mice.

Abstract

Conjugated linoleic acid (CLA) is a naturally occurring group of dienoic derivatives of linoleic acid found in beef and dairy products. CLA has been reported to reduce body fat. To examine the mechanism(s) of CLA reduction of fat mass, female C57BL/6J mice were fed standard semipurified diets (10% fat of total energy) with or without CLA (1% wt/wt). Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick endlabeling (TUNEL) and DNA fragmentation analysis revealed that fat-mass decrease by CLA was mainly due to apoptosis. Tumor necrosis factor (TNF)-␣ and uncoupling protein (UCP)-2 mRNA levels increased 12-and 6-fold, respectively, in isolated adipocytes from CLA-fed mice compared with control mice. Because it is known that TNF-␣ induces apoptosis of adipocytes and upregulates UCP2 mRNA, a marked increase of TNF-␣ mRNA with an increase of UCP2 in adipocytes caused CLA-induced apoptosis. However, with a decrease of fat mass, CLA supplementation resulted in a state resembling lipoatrophic diabetes: ablation of brown adipose tissue, a marked reduction of white adipose tissue, marked hepatomegaly, and marked insulin resistance. CLA supplementation decreased blood leptin levels, but continuous leptin infusion reversed hyperinsulinemia, indicating that leptin depletion contributes to the development of insulin resistance. These results demonstrate that intake of CLA reduces adipose tissue by apoptosis and results in lipodystrophy, but hyperinsulinemia by CLA can be normalized by leptin administration. Diabetes 49:1534-1542, 2000 C onjugated linoleic acid (CLA) is a group of positional and geometric isomers of conjugated dienoic derivatives of linoleic acid. The major dietary sources of CLA for humans are beef and dairy products (1). There is a great interest in CLA because of its anticarcinogenic and antiatherogenic properties and its ability to reduce body fat while enhancing lean body mass (2). Reduction of body fats by CLA was observed in pigs (3), mice (4,5), and hamsters (6).In this study, we investigated the mechanism(s) of CLAmediated reduction of fat mass in mice. Reduction of fat mass by CLA was due to apoptosis. Initially, we expected the beneficial effect of CLA-induced fat mass decrease, such as improvement of insulin resistance and reduction of blood triglyceride concentration. Unexpectedly, however, rapid reduction of fat mass by CLA resulted in marked insulin resistance and hepatomegaly. These metabolic abnormalities are characteristics of lipodystrophy (7,8). During this study, Delany et al. (9) also reported that CLA reduced body fat but resulted in hyperinsulinemia and liver enlargement in AKR/J male mice. To understand the mechanism(s) of CLAinduced lipodystrophy, we examined expression levels of several genes important in energy expenditure and lipid and carbohydrate metabolism in adipose tissues and isolated adipocytes. Furthermore, effects of leptin infusion on CLAinduced insulin resistance were also examined. RESEARCH DESIGN AND METHODSExperimental protocols. Female C57BL/6J mice were obt...

Conjugated linoleic acid (CLA) and obesity

“…Trans-10,cis-12 CLA also inhibits the expression of glucose transporter-4 (GLUT-4) 37,38 and increases the activity of carnitine palmitoyltransferase (CPT), enhancing fatty acid oxidation 10 . Trans-10,cis-12 CLA reduces lipogenesis in human 37 and mice adipocytes, decreasing sterol regulatory element-binding protein-1 (SREBP-1) expression in vivo 39 . Trans-10,cis-12 CLA also induces adipocyte apoptosis in mice [39][40][41][42][43] , perhaps mediated by an increase in tumour necrosis factor alpha (TNFa) 39 , but the effects of CLA on lipolysis in vivo and in vitro are conflicting 10,38 .…”

“…Trans-10,cis-12 CLA reduces lipogenesis in human 37 and mice adipocytes, decreasing sterol regulatory element-binding protein-1 (SREBP-1) expression in vivo 39 . Trans-10,cis-12 CLA also induces adipocyte apoptosis in mice [39][40][41][42][43] , perhaps mediated by an increase in tumour necrosis factor alpha (TNFa) 39 , but the effects of CLA on lipolysis in vivo and in vitro are conflicting 10,38 . Data regarding its effects on preadipocyte differentiation are inconclusive, possibly depending on species, CLA isomer and experimental conditions 4,37 .…”

“…However, some studies show an increase in UCP2 expression (mostly with trans-10,cis-12 CLA supplementation) in brown and white adipose tissue and skeletal muscle 39,47,48 .…”

The effect of trans-10,cis-12 conjugated linoleic acid on lipogenesis is tissue dependent in hamsters

“…In contrast, Azain et al [4] did not find changes in FAS activity induced by CLA feeding in rats. Other authors found reduced expression of FAS and ACC in mice [5,6] . In the present work, trans-10,cis-12 CLA feeding significantly reduced the mRNA expression of the two specific lipogenic enzymes measured (ACC, FAS).…”

“…Concerning the effects of CLA on liver, several studies in mice have shown that trans-10,cis-12 increased liver weight [8][9][10][11][12][13]. In some of these trials, hepatic triacylglycerol content was measured and it was concluded that hepatomegaly was due to lipid accumulation [5,[14][15][16]. In contrast, the studies performed on rats reported no effects on liver weight induced by CLA [4,10,[17][18][19][20].…”