Friday, June 7, 2013

Gut Bacteria in the Control of Obesity and Type 2 Diabetes

The bacteria (microbiota) that reside in our intestines were once thought to be of little consequence except for their role in vitamin synthesis. However, very recently a new area of study has begun to focus on the role of the bacterial complement of the gut and the role these microorganisms play in altering dietary and metabolic processes. Of particular significance is the now recognized alteration in gut microbiota associated with obesity, type 2 diabetes, and the associated increase in intestinal inflammation and gut barrier disruption this causes.

For more information on the correlation between obesity and gut bacteria visit the Obesity page of themedicalbiochemistrypage.org

A recent paper in this field, published in the Proceedings of the National Academy of Sciences, has demonstrated that a particular strain of gut bacteria, Akkermansia muciniphila, is directly involved in the control of diet-induced obesity. A. muciniphila is a Gram-negative bacteria (i.e., it contains LPS) that constitutes 3–5% of the gut microbiota. 

Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity

A. muciniphila is a mucin-degrading bacterium that resides in the mucus layer of the intestinal tract. Strikingly, there is an inverse correlation in humans between the levels of this bacterium and body weight.

Earlier studies by this same group examined the changes in gene expression within the gut of germ-free mice inoculated with A. muciniphila. What they discovered was that genes involved in pathways that regulate lipid metabolism, cell signaling, and molecular transport activated by this bacterium

This most recent study utilized mouse models of obesity and diabetes to define the role of A. muciniphila in these disorders. They found that the levels of A. muciniphila were decreased in obese and type 2 diabetic mice. Of potential clinical significance was their finding that prebiotic feeding normalized A. muciniphila levels and this change could be correlated with an improved metabolic profile in these animals. Prebiotics are non-digestible food ingredients (primarily carbohydrates) that stimulate the growth and/or activity of beneficial bacteria in the gut.  Another result of this study was that A. muciniphila treatment reversed many of the metabolic dysfunctions that result from a high-fat diet including fat-mass gain, adipose tissue inflammation, and insulin resistance. 

The administration of A. muciniphila to these mice was also shown to result in increased intestinal levels of endocannabinoids. Gut endocanabinoids control intestinal inflammation, stimulate gut barrier functions, and increase gut peptide secretion. Important gut peptides stimulated to be released by endocannabinoids are glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2). GLP-1 is involved in glucose homeostasis via its actions on the pancreas and it is involved in the control of appetite via actions within the brain. GLP-2 is involved in the regulation of gut barrier function.

More information on the roles of the endocanabinoids

More information on the functions of GLP-1

The results of this research provide a strong rationale for the use of prebiotics that stimulate the density of A. muciniphila in the gut, and/or for treatments that utilize this strain of bacteria for the prevention or treatment of obesity and its associated metabolic disorders.

Monday, June 3, 2013

Adipose (fat) Tissue Lipid Chaperone, aP2, Regulates Liver Glucose Homeostasis

Adipose tissue is much more than just the fat storage organ. Mature adipocytes synthesize and secrete numerous enzymes, growth factors, cytokines (referred to as adipokines) and hormones that are involved in overall whole body energy homeostasis. There are currently over 50 different adipokines recognized as being secreted from adipose tissue. These adipokines are implicated in the modulation of a range of physiological responses that globally includes appetite control and energy balance. Specific metabolic processes regulated by adipose tissue include lipid metabolism, glucose homeostasis, inflammation, angiogenesis, hemostasis, and blood pressure. For more details on the functions of adipose tissue go to the Adipose Tissue page of themedicalbiochemistrypage.org.

Indeed, adipose tissue is a critical organ for storage of energy in the form of triglycerides. Upon hormonal demand the fatty acids f triglycerides are released to the circulation where they can by absorbed by other tissues and oxidized to produce needed ATP. The processes of lipid storage and release from adipose tissue are complex and involve numerous proteins and enzymes associated with the fat droplets inside adipocytes. New evidence, just recently published in the journal Cell Metabolism, demonstrates that a protein that was once thought to have a primary function as a lipid chaperone within adipocytes (the fatty acid binding protein called aP2, also called fatty acid binding protein 4, FABP4) is actually also a secreted factor of adipose tissue and that when secreted exerts effects on the liver leading to increased glucose output.

Adipocyte Lipid Chaperone aP2 Is a Secreted Adipokine Regulating Hepatic Glucose Production

As a brief background, intracellular fatty acid homeostasis involves a number of factors and two of these in adipose tissue are the adipose fatty acid binding proteins (FABPs) aP2 (FABP4) and FABP5, where aP2 is the major binding protein in this tissue. Previous experiments have demonstrated that mice deficient in these lipid chaperones are protected against many of the metabolic abnormalities associated with obesity. Also, previous experiments by the authors of the above linked manuscript have shown that aP2 deficient adipose tissue results in altered glucose production by the liver. These observations showed that the effects were not due to leptin or adiponectin, two of the major adipose tissue hormones.

The current publication shows that aP2 is secreted from adipose tissue in response to fasting and that this secretion results in regulation of hepatic glucose production. In the experimental mice, depletion of serum aP2 results in suppression of hepatic glucose production, whereas, elevation of serum aP2 in these mice leads to enhanced hepatic glucose production. Of clinical significance to humans is that aP2 secretion and serum levels are positively correlated  with obesity.

The results of this publication demonstrate that aP2 is actively secreted from adipocytes and then acts on the liver to regulate glucose output. Significantly, the level of aP2 secretion from adipose tissue increases in obesity which leads to further increases in already elevated blood levels of glucose typical of obesity due to obesity-mediated insulin resistance and the development of type 2 diabetes. Of significance to this latter fact is that in experimental mice, neutralization of secreted aP2 results in reduced hepatic glucose output.

aP2 lacks a signal peptide, therefore it is likely that its secretion occurs through a non-classical mechanism. In obesity, adipose tissue inflammation is enhanced and this is associated with cell death (apoptosis) which may contribute to the high levels of aP2 in circulation. Thus, obesity-induced elevations in serum aP2 levels might contribute to the elevated hepatic glucose production, which is the hallmark of hyperglycemia, in subjects with type 2 diabetes typically associated with obesity.

Let me point out the significance of this observation. Adipose tissue expands in obesity and this expansion is associated with increased secretion of pro-inflammatory adipokines. The effects of these inflammatory adipokines are broad and ultimately result in exacerbation of the resistance to insulin which is a major metabolic complication in obesity leading to type 2 diabetes. One of the most significant problems of obesity, insulin resistance, and type 2 diabetes is hyperglycemia. indeed, all of the current pharmacological therapies for type 2 diabetes are aimed at reducing the level of glucose in the blood. So, with an expanding adipose tissue in obesity there is an increased release of aP2 and as a result a further increase in the hyperglycemia due to the stimulation of hepatic glucose production by this adipokine. The observations of this paper indicate that aP2 may very well be another target for pharmacological intervention in the treatment of type 2 diabetes.