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Fat: The largest endocrine organ (Proceedings)

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Apr 01, 2009

Adipokines

The past decade has seen a revolution in our understanding of adipose tissue. The functions of fat have traditionally been understood as energy storage, thermal insulation, and structural support for some organs. It is now known that adipose tissue is metabolically active and constitutes the largest endocrine organ in the body with unlimited growth potential at any stage of life. Recognizing that adipose tissue is not inert has helped us understand the complex relationship between obesity and some of the diseases associated with obesity in humans (i.e., heart disease, diabetes and chronic degenerative joint disease).

The relationship of obesity to other types of diseases, such as type 2 diabetes mellitus, is not easily understood. The link is a group of proteins, collectively called adipokines, which are secreted by adipose tissue and adipose-resident macrophages and fibrocytes. Adipokines exert their effects in the central nervous system and peripherally, in tissues such as skeletal muscle and the liver. Leptin, adiponectin, resistin, visfatin, retinol-binding protein and tumor necrosis factor-alpha (TNFalpha) are some of the main adipokines of interest. Enzymes such as lipoprotein lipase are also abundantly produced and released from adipose tissue. Finally, many pro-inflammatory cytokines and acute-phase proteins originate in adipocytes.

Of the adiopkines, leptin has received the most attention. In 1995, leptin was identified as the fat cell-specific secretory factor that mediates the hormonal axis between fat and the brain. Leptin concentrations increase with increased body fat in all species studied including dogs and cats. Adequate energy stores are signaled by leptin and permit reproduction and normal immune function. Leptin also functions to reduce appetite. Despite high hopes that leptin would be the long-sought "lipostat", it is now known that leptin resistance develops with increasing obesity. The ability of low leptin levels to stimulate appetite is greater than the ability of high leptin levels to suppress appetite. Leptin, however, may provide a link between osteoarthritis and obesity. In humans, increased leptin in synovial fluid has been seen in patients with either rheumatoid arthritis or osteoarthritis.

Genomics and Obesity

As indicated earlier, the relationship of obesity to other diseases is complicated and only recently is being recognized as a key factor affecting overall health. New research tools such as genomics have enabled scientists to shed some light on the underlying mechanisms which link obesity with other diseases. By performing microarray analysis on lean and obese adipose tissue and lymphocyte samples, scientists have begun to understand the processes behind obesity and, importantly, how obesity links to other diseases.

When comparing lean vs obese adipose tissue, the gene expression of obese adipocytes showed a down regulation of PPAR-gamma, uncoupling protein-2, carnitine O-palmitoyltransferase 1 A and acyl-CoA synthetase. When functioning properly these genes are important in the beta-oxidation of fatty acids. The down-regulation of these genes may explain why obese animals are fat storing instead of fat burning. In addition, the obese adipose tissue also had down-regulation of genes associated with glucose metabolism. Down-regulation of pyruvate dehydrogenase kinase-4 and glucose-6-phosphatase may be a potential link between diabetes and obesity.

Many of the same pathways altered in the obese adipose tissue have also found to be altered in lymphocytes from obese dogs. Microarray analysis of lymphocytes revealed that overweight dogs had decreased carbohydrate metabolism, interleukin signaling, PPAR signaling, IGF-1 signaling, insulin receptor signaling, amino acid metabolism, branch chain amino acid degradation and lipid metabolism compared to results of similar analyses in lean dogs. These observations of both adipocytes and lymphocytes may explain why obese animals become insulin resistant and have increased circulating glucose, insulin, IGF-1 and inflammation.