Wednesday, August 22, 2012

Obesity Makes You Older

There is no question that being overweight or obese plays havoc with the human body. From the simple fact of the strain on joints from carrying around all that weight to the complex interplay between excess fat and the development of diabetes, heart disease, cancer, kidney failure, central nervous system dysfunction, etc. etc.

Now a recent study published in the journal Cell Metabolism, demonstrates that excess fat tissue (adipose tissue) disrupts the normal functioning of a special family of proteins called sirtuins (SIRTs) specifically adipose tissue SIRT1: http://dx.doi.org/10.1016/j.cmet.2012.07.003

Sirtuins have been the focus of intense scrutiny since the discovery that the yeast sirtuin gene, Sir2, functions as a longevity factor. In other words the expression of Sir2 is associated with life span in yeasts. And expression of yeast Sir2 is enhanced during periods of calorie restriction which has led to speculation that mammalian sirtuin proteins may also be associated with longevity associated with calorie restricted diets. The sirtuins function as either deacetylases or ADP ribosylases, and their activity is regulated by the cofactor NAD and thus may serve as sensors of the metabolic state of the cell and organism. Humans possess 7 sirtuin genes SIRT1-SIRT7. Studies have shown that the anti-oxidant compound resveratrol, found at high concentrations in red wine, can enhance sirtuin activity in cells in culture. The story is less clear in whole animals and humans but the potential for resveratrol as an anti-aging compound is left for another discussion. If you want to read more about resveratrol visit my Supplement Science website.

In the present study it is demonstrated that SIRT1 in adipose tissue functions to protect from inflammation and obesity under normal feeding conditions. This function of SIRT1 delays the progression to metabolic dysfunction that occurs under conditions of dietary stress (e.g. high fat diets) and aging. In mice that have the SIRT1 gene knocked out specifically in adipose tissue, there is a change in the pattern of gene expression in this tissue that is similar to the pattern of changes seen in wild-type mice fed a high-fat diet. This suggests that dietary stress signals to inhibit the activity of SIRT1. Indeed, in this study wild-type mice fed a high-fat diet showed induction of SIRT1 cleavage by the inflammation-activated caspase, caspase-1.

The take home from these studies is that adipose tissue SIRT1 is necessary for the maintenance of metabolic health in adipose tissue. The consumption of a high-fat diet, or consumption of a diet with excessive calories leading to obesity leads to an inactivation of SIRT1 via inflammation-induced cleavage. The loss of SIRT1 function in adipose tissue significantly contributes to the diabetic phenotype consisting of whole-body glucose intolerance and insulin resistance.

Given the potential role for sirtuins in modulating the processes of aging and age-related disease it seems likely that obesity not only leads to diabetes and heart disease, etc. but also likely causes whole body aging. Of course obese individuals generally die from the metabolic complications of diabetes, heart failure, and kidney failure so it may be difficult to ascertain the precise role that loss of adipose tissue sirtuin function plays in the overall consequences of being obese or overweight.

Tuesday, August 7, 2012

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.

Sunday, August 5, 2012

Consumption of Brown Rice Reduces Desire for Fat

In the US, as well as many other countries, grains such as rice, make up a significant part of the average persons diet. However, during the process of refining grains like rice, as well as wheat and barley etc., the outer parts (bran) are removed. The bran contains multiple nutrients and bioactive compounds that are thus lost to our diets. Many recent studies have demonstrated diets rich in whole grains improve insulin responsiveness and reduce the incidence of type 2 diabetes. Brown rice is indeed one of the grains known to exert this positive effect on the prevention of diabetes. Until recently, although it was known that consumption of brown rice exerted these effects, it was not clear as to what was the mechanism of these effects of brwon rice.

The bran of brown rice, like all grain brans, is rich in antioxidants, phytosterols, and other beneficial nutrients. One of the more bioactive components of brown rice is known as gamma-oryzanol which is a mixture of ferulic acid esters and phytosterols. Ferulic acid is a hydroxycinnamic acid which is an  abundant phenolic phytochemical found in many plants.

A recent study published online in the journal Diabetes, (http://diabetes.diabetesjournals.org/content/early/2012/07/11/db11-1767.abstract?sid=78185278-fee8-452d-81e4-8c3dd1822305) now shows that the mechanism of action  of brown rice, and in particular gamma-oryzanol, is via the prevention of cellular stress within the region of the brain called the hypothalamus. The hypothalamus is the major appetite and energy expenditure regulatory structure in the brain. For more information on how the hypothalamus regulates appetite and feeding behaviors visit the Gut-Brain Interactions page at themedicalbiochemistrypage.org.

When laboratory mice given free access to a diet that consisted of brown rice-containing chow as well as a chow that was high in fat the mice significantly preferred to eat only the brown rich chow and ignored the high fat chow. This result indicates a strong correlation between consumption of whole grains such as brown rice and a decrease in the desire to consume fatty foods. This same result was obtained with mice if they were orally administered gamma-oryzanol. In addition to the effects on food preference by consumption of brown rice, the mice exhibited improved glucose tolerance and showed a reduction in endoplasmic reticulum (ER) stress within the hypothalamus. When the mice were administered 4-phenylbutyric acid, which is a chemical chaperone that prevents ER stress they preferred the brown rice chow over the high fat chow and exhibited increased glucose tolerance. These results suggest that gamma-oryzanol likely functions as a chemical chaperone and prevents ER stress in the hypothalamus thus resulting in the altered feeding behaviors. Of note is that ferulic acid itself is known to produce a reduction on ER-stress when added to nerve cells in culture. It is also important to point out that the consumption of brown rice did not result in alterd levels of circulating insulin indicating that the altered dietary preferences were insulin-independent.

When the expression of ER stress genes was analyzed in these studies, brown rice-fed mice demonstrated a significnat reduction overall expression within the hypothalamus. Increases in hypothalamic ER stress are known to provoke resistance to leptin resulting in increased feeding and ultimately obesity. In addition, hypothalamic ER stress is known to cause an increased preference for a fatty diet.

The major take-home from this study is that the principal mechanism by which the known effects of whole grains and brans on glucose tolerance and diabetes, is exerted via the attenuation of ER stress within the major appetite and feeding control center of the brain, the hypothalamus.