Thursday, May 16, 2013

Obesity Causes Abnormal Processing of Appetite Suppressing Proteins in the Brain

The hypothalamus is a small structure in the brain yet it is responsible for major regulation of feeding behaviors. Neuropeptides produced by neurons in the hypothalamus dictate whether one feels hungry and will stimulate feed seeking behavior whereas other neuropeptides produced by other neurons in the same structure let us know we are full and give us the sensation of feeling full. There are proteins made in cell of the gastrointestinal system that communicate with the hypothalamus and in so doing integrate feeding behavior responses in concert with the brain. For more details on the interrelationships between the gut and the hypothalamus in the regulating feeding behaviors see my page Gut-Brain Interrelationships and the Control of Feeding Behaviors at the Medical Biochemistry Page.

One of the hypothalamic neuropeptides involved in the sensation of satiety (feeling full and therefore not desiring food) is called alpha-melanocyte stimulating hormone (a-MSH) and it is derived through cell-type specific enzymatic processing from the precursor protein, pro-opiomelanocortin (POMC). a-MSH is member of the melanocortins which are derived from POMC. Genetic mutations in humans as well as in animals that disrupt the expression and processing of POMC peptides are associated with changes in energy balance and can lead to obesity and type 2 diabetes. In humans there have been mutations identified in prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE), as well as in the a-MSH degrading enzyme prolylcarboxypeptidase (PRCP) that are associated with energy imbalance and a propensity for obesity.

Now a just published report in the Journal of Biological Chemistry demonstrates that obesity can lead to a vicious spiral of more eating and worsening of obesity due to changes in the hypothalamic processing of a-MSH from POMC.

Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing

Previous studies by the same group had shown that diet-induced obesity (DIO) is associated with decreases in hypothalamic a-MSH levels but that the level of the mRNA for the precursor protein, POMC remain unaltered. The current study goes on to show that DIO induces endoplasmic reticulum (ER) stress which plays a role in the regulation of energy balance. When the ER becomes stressed because of an excessive accumulation of newly synthesized unfolded proteins, the unfolded protein response (UPR) is activated. These UPR pathways in the pancreas are associated with impaired insulin processing. Within the hypothalamus the UPR impairs the processing of a-MHC from POMC due to defects in the enzyme prohormone convertase 2 (PC2).

The net effect of DIO on hypothalamic feeding circuits is, unfortunately, a decreased ability to respond normally to what should be a normal cessation of the desire to eat, resulting in more eating, and more obesity. As these authors point out, our ability to more accurately dissect the central control of energy-regulating neuropeptides during DIO will be critical to the development of new therapeutic targets to prevent and/or mitigate obesity and its associated pathophysiology such as the development of type 2 diabetes.

Friday, May 3, 2013

Tumor Growth Inhibited by the Omega-3 PUFA DHA (docosahexaenoic acid)

As I have indicated in my blog on several occasions, consumption of the omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is one of the many important aspects of a healthy diet and lifestyle. You can of course read more information about these fats on  The Medical Biochemistry Page in the Omega Fatty Acids page.

Now a recent publication in the prestigious journal, Proceedings of the National Academy of Sciences demonstrates yet another blockbuster benefit to the consumption of these omega fats.

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

Numerous studies in both humans and laboratory animals have shown that omega-3 PUFAs can reduce the risk for certain types of cancers, however, the precise mechanism(s) by which these fats exert these effects is not completely understood. What is known, with respect to cancer, is that omega-3 PUFAs can inhibit the formation of new blood vessels, the process termed angiogenesis. Tumors require large amounts of nutrients and oxygen to grow and they accomplish this by stimulating the process of angiogenesis.

This most recent study has demonstrated that metabolic by-products of DHA (epoxydocosapentaenoic acids, EDPs), that are generated by normal hepatic cytochrome P450 (CYP) enzyme activity, inhibit VEGF- (vascular endothelial growth factor) and FGF-2- (fibroblast growth factor 2) induced angiogenesis. An additional striking and clinically significant finding from these studies was that the corresponding cytochrome P450 derived metabolites from the omega-6 PUFA, arachidonic acid (these metabolites are epoxyeicosatrienonic acids) actually stimulate angiogenesis and tumor progression.

These results also demonstrated that the epoxy metabolites of DHA are potent vasodilators and potent anti-inflammatory agents. The significance of the vasodilatory effects of DHA-derived epoxy metabolites stems from the fact that previous research has shown that targeting VEGF with inhibitors to restrict tumor-derived angiogenesis results in the induction of hypertension. Therefore, the DHA-derived epoxy metabolites may have unique advantages in antiangiogenic cancer therapy by avoiding the hypertension associated with VEGF inhibition.

The ideal diet of omega fatty acids is suggested to be in a 2:1 ratio of omega-6 to omega-3 PUFAs. However, in the typical Western-style diet that ratio is closer to 20:1. Now it is important to note that arachidonic acid is a good omega-6 PUFA as it is important in promoting the normal processes of inflammation (for example), however, in excess the consequences are excess inflammatory processes which contribute to obesity, diabetes, heart disease, and cancer. This latest research finding indicates one important mechanism by which too much omega-6 PUFA can, and likely, contributes to higher rates of certain types of cancer.