Obese but Healthy, Is it True?

It is true for the vast majority of obese individuals that these people will develop type 2 diabetes (T2D), cardiovascular diseases such as atherosclerosis, and other chronic health problems. However, it has always been a scientific and clinical curiosity that a small percentage of overweight or obese individuals do not develop these same symptoms. In addition, it is known that certain thinner individuals may develop the types of health problems more typical of those associated with obesity.

In the realm of obesity and diabetes research it has long been known that excess circulating fatty acids, as is typically seen in overweight and obese subjects, is associated with enhanced cellular and systemic inflammation. In addition, this enhanced state of inflammation results in insulin resistance and the development of T2D. For more information on inflammation and insulin resistance see the Insulin Function page on my website.

For a short introduction to the heart of this posting it is necessary for me to introduce you to an inportant enzyme involved in the regulation of glucose (sugar) metabolism. The details of which can be found in the Glycolysis page of my website. Control over the rate of glucose oxidation  for energy production  and the synthesis of new glucose, for periods such as fasting or starvation, is exerted upon the rate-limiting enzymes 6-phosphofructo-1-kinase (phosphofructokinase-1, PFK-1) and fructose-1,6-bisphosphatase (F1,6BPase). This control is effected by the potent allosteric regulator fructose-2,6-bisphosphate (F2,6BP). F2,6BP is synthesized, as well degraded (hydrolyzed) bythe bi-functional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (most commonly abbreviated PFK-2, or PFK-2/F2,6-BPase). Humans possess four PFK-2 genes and each gene encodes several isoforms. The gene relevant to this discussion is most highly expressed in the brain and placenta and is identified as the PFKFB3gene. The gene encodes two distinct isoforms due to alternative splicing with one form being expressed at very low levels in most tissues but its' expression is induced by pro-inflammatory stimuli. This PFK-2 isoform is, therefore, identified as the inducible PFK-2 (iPFK-2). Research over the past several years has demonstrated that iPFK-2 expression may be linked to the metabolic and inflammatory events that underlie the concept of "healthy" obesity.

Earlier work with iPFK-2 demonstrated that global inhibition of its expression in mice resulted in a reduction in diet-induced obesity but also resulted in an exacerbation of adipose tissue inflammation and enhanced insulin resistance. Most recently the same laboratory carried out the opposite experiment directed at enhanced expression of iPFK-2. When iPFK-2 is overexpressed in adipose tissue of mice two observations were made. First there was an increase in fat deposition and secondly (and of critical clinical importance) there was a suppression of adipose tissue inflammatory responses. These two events lead to improved insulin sensitivity in both adipose tissue and the liver. The increase in fat deposition in these animals equates to obesity, but the reduced inflammation and increased insulin sensitivity equates to protection from the harmful consequences of obesity. Therefore, these results demonstrate that the level of expression of iPFK-2 may indeed be a critical component of what is referred to as healthy obesity. Given these results, published in the Journal of Biological Chemistry, strongly indicate that targeting iPFK-2 activity may be a potent weapon in the battle against the adverse effects of obesity and the resultant T2D.

http://www.jbc.org/content/early/2012/05/03/jbc.M112.370379.abstract?sid=492f7317-9586-4733-8053-6cb8594f0a82

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