Dietary n-3 and n-6 polyunsaturated fatty acids differentially modulate the adiponectin and leptinmediated major signaling pathways in visceral and subcutaneous white adipose tissue in high fat diet induced obesity in Wistar rats.

Obesity is a chronic metabolic disease that involves excessive accumulation of fat in white adipose tissue (WAT). Apart from storing excess fats, WAT also serves as an important endocrine organ secreting adipocytokines such as adiponectin and leptin. Adiponectin and leptin bind to their transmembrane receptors adiponectin receptor 1 (AdipoR1)/adiponectin receptor 2 (AdipoR2) and Ob-R , respectively, and mediate their effect on metabolism by regulating multiple downstream targets. Dietary fat is considered the main culprit behind obesity development. Numerous preclinical studies have highlighted role of essential polyunsaturated fatty acids (PUFAs), particularly n-3 PUFAs, in prevention of obesity. Despite emerging data, there still is no clear understanding of the mechanism of action of n-3 PUFAs and n-6 PUFAs on adipose tissue function in two functionally and anatomically different depots of WAT: visceral and subcutaneous. We designed this study using a high fat diet (HFD) fed rodent model of obesity to test our hypothesis that n-3 and n-6 PUFAs possibly differentially modulate adipokine secretion and downstream metabolic pathways such as peroxisome proliferator-activated receptor-γ (PPAR-γ), protein kinase B (AKT)-forkhead box O1 (FOXO1), and Janus kinase-signal transducer and activator of transcription in obesity. The results of the current study showed that n-3 PUFAs upregulate the expression of AdipoR1/R2 and ameliorate the effects of HFD by modulating adipogenesis via PPAR-γ and by improving glucose tolerance and lipid metabolism via AKT-FOXO1 axis in fish oil fed rats. However, n-6 PUFAs did not show any remarkable change compared with HFD fed animals. Our study highlights that n-3 PUFAs modulate expression of various targets in adiponectin and leptin signaling cascade, bringing about an overall reduction in obesity and improvement in adipose tissue function in HFD induced obesity. Graphical representation of effect of n-3 and n-6 PUFAs on white adipose tissue function in high-fat-diet–induced rodent model of obesity. n-3 PUFA supplementation led to an increased expression of adiponectin receptors AdipoR1/R2, resulting in activation of downstream targets PPAR-γ and AKT with specific inhibition of FOXO-1 in subcutaneous WAT, resulting in a beneficial effect on high-fat-diet–induced obesity by increasing adipogenesis, energy expenditure, lipid oxidation, glucose metabolism, and suppression of inflammation. n-6 PUFA supplementation did not show any improvement in adiponectin/leptin mediated signaling. The green arrows signify increased levels and red arrows signify decreased levels. Dotted arrows signify no effect on the downstream target. ACC, acetyl-CoA carboxylase; AdipoR1, adiponectin receptor 1; AdipoR2, adiponectin receptor 2; AKT, protein kinase B; AMPK, AMP-activated protein kinase; FOXO1, forkhead box O1; HFD, high-fat diet; JAK-2, Janus kinase 2; Ob-R, leptin receptor; PGC1α, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha; PI3K, phosphoinositide 3-kinase; PPAR, peroxisome proliferator-activated receptor; PUFA, polyunsaturated fatty acid; STAT3, signal transducer and activator of transcription 3; SWAT, subcutaneous white adipose tissue; UCP1, uncoupling protein 1; WAT, white adipose tissue. [Display omitted] [ABSTRACT FROM AUTHOR]