Tuesday, July 16, 2013


Several hormones and bioactive peptides are secreted from specialized cells within the gastrointestinal tract. The stomach and small intestines are the major sites for the secretion of these proteins. Several of these factors, following release to the blood stream, have been known for some time to exert effects within the central nervous system that affect our desire to eat and also the level of satiety experienced following the consumption of food. These gut appetite regulating proteins are of two types: those that inhibit the desire for food are called anorexigenic factors, while those that stimulate our desire for food are called orexigenic. The majority of gut proteins that exert effects on appetite and satiety are anorexigenic, whereas, there is but a single gut peptide (ghrelin) that acts in an orexigenic manner in the brain. The anorexigenic gut peptides include protein tyrosine tyrosine (PYY), pancreatic polypeptide (PP), cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and apolipoprotein A-IV (apoA-IV).

For more details on the role of gut peptides in the regulation of appetite and feeding behaviors visit the Gut-Brain Interrelationships page of my web site.

A recent paper just e-published in the journal Obesity demonstrates that administration of two of these anorexigenic gut hormones PYY and PP in combination results in reduced feeding behavior in an additive manner in laboratory mice paving the way for their potential use in the treatment of obesity in humans.

Both PYY (the biologically active circulating form of PYY is called PYY3-36 because it contains amino acids 3-36 of the primary translation product of the PYY gene) and PP have previously been shown to potently inhibit food intake both animals and humans. The results of this study demonstrate that addition of both of these gut peptides simultaneously results in an inhibition of feeding behavior that is additive. In other words the repression of appetite in lab animals was significantly higher in mice receiving both hormones compared to mice receiving either hormone alone. These effects were exerted via two distinct neuronal pathways in the hypothalamus. The hypothalamus is a region of the brain critically involved in the integration of metabolic demands of the body with the stimulation or repression of appetite and feeding behaviors.

The take home from this study is that there is great potential for the use of combination therapies such as co-administration of PYY and PP agonists in the treatment of obesity. The advantages of dual administration therapies is that the doses of either compound could be reduced to lessen any potential for untoward side-effects, while still maintaining potent regulation of appetite and weight gain.

Monday, July 8, 2013

Fructose in the Diet Leads to Fatty Liver & Promotes Metabolic Disease

The amount of fructose in the typical American diet has increased dramatically in the past 20 years. This is due primarily to the increased use of high fructose corn syrup (HFCS) as a sweetener is processed foods and drinks, especially soft drinks. The use of HFCS as a sweetener stems from the fact that the US grows significantly more corn than sugar beets or cane sugar and it is relatively easy and inexpensive to chemically convert some of the glucose in corn starch (starch being a polymer of glucose) to fructose. Consumption of soft drinks (high in HFCS) is associated with an increased risk for obesity in adolescents and for development of type 2 diabetes in young and middle-aged women. Excess fruit juice (also rich in fructose) is also associated with the development of obesity in children. One cannot, however, assume that the culprit is exclusively HFCS. In the typical Western-style diet there is an overall excess of caloric intake that contribute to obesity, diabetes, heart disease, and numerous other ailments. However, this is not to say that fructose is an “innocent” molecule. Indeed, consumption of fructose has been shown to be highly correlated with the development of diabetes, fatty liver diseases, obesity and the metabolic syndrome. Consumption of soft drinks (high in HFCS) is associated with an increased risk for obesity in adolescents and for type 2 diabetes in young and middle-aged women. Excess fruit juice (also rich in fructose) is also associated with the development of obesity in children. These effects are related to the mechanism of fructose metabolism versus that of glucose and also to the effects of fructose metabolism in the brain on appetite and feeding behaviors. For the details go to the Fructose Metabolism page of themedicalbiochemistrypage.org

New data recently e-published in the American Journal of Clinical Nutrition demonstrates that dietary fructose, even under conditions of normal caloric intake, leads to hepatic damage and endotoxemia contributing to the development of hepatic steatosis (fatty liver) and non-alcoholic fatty liver disease (NAFLD). This is significant because hepatic steatosis is highly correlated with diabetes and cardiovascular disease.

This research is significant to human health for a number of reasons, the most importnat being that the data was acquired with the use of primates and not mice which are the more commonly used mammalian model. The other significant fact is that the damaging effects of fructose were observed even when the animals were fed a normal caloric diet.

The experiments performed in this published study demonstrated that high dietary fructose consumption rapidly induces liver fatty infiltration, inflammation, and damage. Significantly, these hepatic changes were shown to occur in a short time period and under conditions when the caloric intake was controlled and there were no changes in the gut microbiome, overall levels of adiposity, or development of signs of the metabolic syndrome.

The take-home from these studies is that even if one carefully watches the total calories consumed in order to maintain a normal body mass index (i.e. low total adiposity), if too many of the calories are delivered in the form of fructose, either as HFCS or sucrose (a disaccharide of glucose and fructose) metabolic disruption and disease can result.