Inhibition of Adipose Tissue Lipid Synthesis May Hold the Key to Obesity Treatment

The consumption of excess calories, whether they be in the form of fat, sugar (carbohydrates), or protein, will result in a progressive increase in fat deposition resulting, ultimately, in obesity. Obesity is currently an epidemic in the US with overall costs that include added health care, lost wages, and the costs associated with the accomodation of overweight and obese individuals, is fast approaching $1,000,000,000,000 a year: yes that number is correct 1 TRILLION.

It is not surprising then that the study of obesity and potential treatment protocols is a significant part of public and private research efforts. Many attempts have been made to pharmacologically intervene in obesity but little long term success has been obtained, especially without adverse and potentially fatal side effects.

A recent study published in the journal Cell Metabolism presents evidence that there may be another potentially potent target for therapeutic intervention of obesity.  http://dx.doi.org/10.1016/j.cmet.2012.06.013  This study examined the consequences of interference woth critical enzymes involved in the processes of lipid storage in fat tissue (adipose tissue, specifically white adipose tissue, WAT). The process of lipid storage in any cell type including WAT is referred to as lipogenesis. Within adipose tissue, lipogenesis is primarily regulated by a transcription factor called peroxisome proliferator-activated receptor-gamma (PPARg). In addition, PPARg is a major regulator of adipocyte differentiation leading to increased adipose tissue. For more details on the role of PPARg in lipid deposition in adipose tissue visit the PPAR page of themedicalbiochemistrypage.org.

De novo lipogenesis in adipocytes requires the multifuncitonal enzyme, fatty acid synthase (FAS). FAS catalyzes the first commited step as well as performs nearly all of the reactions of de novo fatty acid synthesis using acetyl-CoA as a substrate. The rate-limiting and highly regulated enzyme of fatty acid synthersis is acetyl-CoA carboxylase 1 (ACC1). For all the details of fatty acid synthesis visit the Lipid Synthesis page of themedicalbiochemistrypage.org. Countering the synthesis of fatty acids, and other complex lipids is the process of fatty acid oxidation, primarily via a process referred to as beta-oxidation. FAS has been implicated in obesity and insulin resistance and pharmacologic disruption in fatty acid synthesis has previously been shown to have dramatic effects on overall lipogenesis.

In the current study the researchers knocked out the mouse FAS gene specifically within adipose tissue. In addition, they discovered the role of a previously uncharacterized gene involved in adipose tissue lipid homeostasis which they called PexRAP (peroxisomal reductase activating PPARg). They demonstrate that PexRAP is localized in the specialized organelle called the peroxisome. Within the context of lipid metabolism the peroxisomes are critical for the oxidation of certain complex lipids as well as being involved in bile acid synthesis and the synthesis of a special class of lipids called ether lipids. Details of peroxisomal function in fat oxidation can be found in the Lipid Synthesis page linked above. In addition to genetically removing FAS from adipose tissue, the researchers used antisense oligonucleotide-mediated knock-down of PexRAP via intraperitoneal injection. In these studies mice were fed a high-fat diet and the effects of gene manipulation on adiposity were measured.

Adipose tissue-specific knockout of FAS resulted in a decrease in PPARg expression and as a result, a reduction in adipogenesis. The consequences to the mice were that loss of FAS activity suppressed high-fat diet-induced obesity. This result is not due to a simple loss of de novo fatty acid synthesis within adipose tissue. The inhibition of lipogenesis results in increased levels of thermogenesis which, simply stated, is the oxidation of fats for heat production instead of ATP production. Thermogenesis is normally a function of brown adipose tissue (BAT) but within WAT there can be an induction of brown-like cells called brite or beige adipocytes. This process of "beiging" is a consequence of the loss of PPAGg expression in response to FAS knockout. The result from knockdown of PexRAP were similar to those seen with adipose tissue FAS knockout. There was decreased adiposity, increased thermogenesis, and increased glucose metabolism.

The take home from these studies is that pharamcologic inhibition of FAS or PexRAP may represent novel approaches to the continuing assault on the obesity epidemic in this country.

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