Tuesday, June 5, 2012

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.


Monday, June 4, 2012

Saturated Fats: What NOT to Eat

It has long been known that consumption of saturated fatty acids, as opposed to unsaturated fatty acids, is bad for ones health due to their significant contributions to cardiovascular disease, obesity, and development of type 2 diabetes.

As a short introduction, saturated versus unsaturated with respect to organic compounds like fatty acids refers to the absence (saturated) or presence (unsaturated) of double bonded carbon atoms (written as -C=C-). A carbon can form four bonds with four up to four different atoms. In fats, these other atoms are hydrogens (H) and carbons (C). When the C of a fatty acid is bonded to 3 H, or 2 H and 2 C it is said to be saturated.

The most abundant saturated fatty acid found in the circulation of humans is palmitic acid. This fatty acid contains 16 carbon atoms all of which are fully saturated. Much research has shown that diets rich in saturated fats contributes to the developement of a range of disorders, including type 2 diabetes (T2D). Recently it has been shown that high levels of palmitic acid (also written as palmitate) activate an inflammation pathway, that when activated in the cells of the pancreas that secrete insulin (the beta cells), result in beta cell death. This beta cell death significantly contributes to reduced insulin production and secretion contributing to the overall decline in insulin sensitivity seen associated with obesity and resulting in T2D. This work was recently published in the journal Cell Metabolism:

  • http://dx.doi.org/10.1016/j.cmet.2012.01.023

  • So foods one SHOULD NOT eat due to high levels of palmitic acid:

    #1 palm oil, 41,000mg per 100gm
    #2 shortening
    #3 butter (unsalted is worse than salted!!!)
    #4 lard

    Activity & Weight Loss: It's not Just Exercise you Need

    It is a given that reducing caloric intake while simultaneously increasing ones level of exercise results in significant weight reduction. Research in mice has shown that when the animals are reared in an enriched environment they show improved cerebral (brain) health which is defined as an increased level of neurogenesis, enhanced learning and memory, and resistance to external cerbral insults. Enriched environments for lab mice are defined as those that are larger, have running wheels, mazes, and toys that are changed regularly.

    An additional unexpected finding from these types of experiments was that the animals in the enriched environments were leaner than littermates reared in a standard laboratory housing environment even though both groups of mice were fed identical diets and had free access to the food.

    In research recently published in the journal Cell Metabolism,
  • http://dx.doi.org/10.1016/j.cmet.2011.06.020
  • investigators looked into the role of the enhanced neurogeneis in enriched environment mice. As a background to the results of the study it is important to appreciate that humans, like rodents, contain two distinct forms of fat. White adipose tissue (WAT) is found both subcutaneously (think "beer belly") and viscerally (surrounding the internal organs). WAT is the primary fat storage organ in the body but fat storage is not its only function. Full discussion of WAT function is beyond the scope of this posting but one can find complete details in the Adipose Tissue page of my website. The other type of fat is called brown adipose tissue (BAT). BAT is so-called because it is highly enriched in mitochondria which are loaded with proteins called cytochromes that confer a reddish-brown color to the mitochondria. Until a few years ago it was thought that BAT was only present in new born babies and disappeared after a few months. The primary role of BAT is the process of "adaptive thermogenesis." Adaptive thermogenesis is the process of increased fatty acid oxidation in response to cold. Unlike fat oxidation in WAT which is used to generate ATP energy, fat oxidation in BAT is uncoupled from ATP production and is instead the energy of electron transport in the mitochondria is released as heat. Recent imaging techniques have shown that BAT tissue remains in adult humans and can be induced in response to cold and sympathetic nervous system activation. BAT-like cells are found residing in WAT of rodents and humans and can be identified as such from the expression of the BAT-specific gene UCP-1 (uncoupling protein-1). When these BAT-like cells were examined in mice living in enriched environments it was found that there was an increase in BAT transformation inside WAT. This transformation was associated with resistance to high-fat diet-induced obesity.The increased BAT induction in these animals was demonstrated to be the result of interactions between the hypothalamus and WAT. The hypothalamus is the major feeding and reward center of the brain and as such expresses numerous neurotransmitters that control reward behaviors and feeding behaviors.

    It appears that what is needed for humans is to find the optimal "enriched environment" that is easily attainable to the widest group of individuals as an additional means to fight the obesity epidemic. Whereas, exercise is indeed the best enrichment humans can engae in to fight fat build-up, many individuals can't find access or time to engage themselves, not to mention that obese individuals already have undue strain on their joints such that even mild exercise can be painful.