A Loss of Function of a Key Protein Associated with Severe Early-Onset Mammalian Obesity

There has been a growing body of evidence to suggest an association between early-onset and severe human obesity with a protein and therefore genetic dysfunction. The actual molecular mechanism responsible for this malady has remained somewhat elusive. However, Dr. Masato Asai and his colleagues from the Division of Endocrinology, Department of Medicine at Boston Children’s Hospital at Harvard Medical School, Boston MA have helped to further clarify the biological origin for this serious condition.

One of the pivotal roles of the cell membrane in living cells is providing the medium through which individual cells communicate with their external environment. For complex organisms such as mammals this is especially critical in order for cells to successfully respond to all the chemical signals that are generated in order to maintain and sustain a state of homeostasis – the regulation of an organism’s internal environment to maintain constancy and stability – so vital for survival.

To fulfill this purpose there is a particular class of membrane-bound proteins referred to as G protein-coupled receptors (GPCRs) that modulate cellular responses to a whole host of stimuli. A sub-category of this class of proteins is represented by the melanocortin receptors (MCRs).  Within this group there exists a subset of receptors tied to specific functions as the following table demonstrates –

Receptor Type      Associated Function
MC1R                     Skin Pigmentation
MC2R                     Hypothalamic-Adrenal-Pituitary Axis – responsive to stress in the external environment MC3R, MC4R         Energy Homeostasis
MC5R                      Exocrine Function

Previous studies have implicated MCR4 in connection with mammalian obesity. Furthermore, it has been shown that there are so-called accessory proteins that play an important role in the function of the MCRs that have been described above. One of these accessory proteins, MRAP2, is associated with MCR4. Given these data, MRAP2, produced in the mammalian brain, would make an excellent candidate for further study. Dr. Asai together with his colleagues genetically modified mice to produce an organism with a dysfunctional MRAP2 protein. These animals developed severe obesity at a young age.

Finally, a study of humans with severe early-onset obesity revealed four rare and possibly pathogenic genetically-derived modifications in MRAP2 further suggesting that this protein may be the causative link to this disease. These represent very important findings in regards to this kind of severe obesity in humans. This may prove to have therapeutic value in the future.

The Surprising effect of Gastric Bypass Surgery on Diabetes

Roux-en-Y gastric bypass (RYGB) is a radical surgical intervention that is used for those individuals who suffer from intractable and severe obesity and want desperately to reduce their weight.  Surprisingly, it has been shown that this is also the best approach for the treatment of obesity-related diabetes (Type 2).  It is so effective in this regard that those patients who have successfully undergone this procedure are often able to dispense with their anti-diabetic medication entirely.  It is currently not fully understood how this particular surgical procedure produces this encouraging result.

In RYGB the following surgical modifications are performed –

• The stomach is divided producing a small gastric pouch (GP) that can only accommodate a small amount of food.
• A portion of the small intestine is transected – made into two branches – and one arm of the transection is connected to the GP and is referred to as the Roux limb (RL)
• Both of these branches meet at the so-called “common limb” (CL) and all contents of the GP then proceed through the rest of the digestive tract.

 As a result of these modifications, food entering the esophagus travels to the GP and then to the RL bypassing the remaining part of the stomach – the so-called “distal stomach” (DS) -, the duodenum and part of the jejunum – these areas represent the upper portion of the small intestine.  The RL is thereby exposed to undigested nutrients.  This change may be implicated in the positive effect that this procedure exerts on diabetes. 

In order to further elucidate the mechanism for this change, Dr. Nima Saeidi at the Center for Basic and Translational Obesity Research, Division of Endocrinology at Boston’s Children’s Hospital studied RYGB using the rat as the animal model.   The results of their studies proved very interesting.  They found that within the cells of the tissues of the RL there is a definitive reprogramming of the intestinal metabolism of glucose.  It is important to remember that a key feature of diabetes is the failure of certain body cells to take up glucose from the circulation  and that the serious symptoms  associated with long-term diabetic patients  are directly related to the chronically high levels of glucose in the blood.  This shift in glucose metabolism associated with RYGB was found to include the increased cellular production of an important enzyme involved in glucose metabolism – glucose transporter-1, an increase in glucose uptake, an enhancement of aerobic glycolysis – the metabolic pathway involved in breaking down glucose and a shift in metabolism towards supporting tissue growth.  Furthermore Dr. Saeidi and his team were able to show that this shift in metabolism is directly related to the fact that the RL is exposed to undigested nutrients.

This is an important finding in support of the efficacy of RYGB in dealing with not only obesity but also obesity-related diabetes.  Furthermore, through a further elucidation of the mechanism by which this anti-diabetic effect operates, a clearer picture is generated in regards to an overall understanding of glucose metabolism.

The Biology of Longevity

Most everyone aspires to living a long and healthy life.  There are certain populations of human and individuals who have had the good fortune to enjoy the benefits of longevity.  This reality has raised the inevitable question – how is this possible?  Recently, scientists engaged in basic research in an attempt to answer this question have come to have a greater understanding of the molecular mechanisms that may help account for longevity in animals and especially in humans.

Surprisingly, the animal model that has been used for this work is the tiny invertebrate worm – Caenorhabditis elegans (C. elegans); this organism grows to an adult size of ~ 1 mm and has a natural lifespan of about 20 days.  C. elegans has a rather complex lifecycle in which it goes through three separate larval stages before it reaches adulthood.  The obvious question that comes to mind is – how can using a simple invertebrate such as C. elegans as an animal can ever hope to shed light on human longevity?   Interestingly, the significant metabolic pathways that are implicated in longevity – as we shall describe shortly – are highly conserved in nature and have direct application to the human system.  The advantage of using an animal model with such a short generation span makes it ideal for studying longevity in a controlled laboratory setting.  In addition, there is mutated form of C. elegans that has a lifespan of up to 10 times the normal, or ~ 200 days.  Use of this variant has helped immeasurably in uncovering the molecular mechanisms for this state.

Dr. R. Shmookler Reiss and his associates at Departments of Geriatrics and Biochemistry and Molecular

Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas have devoted a great deal of time and effort in the pursuit of discovering biomarkers that account for this remarkably increased longevity in C. elegans.   In the painstaking process they have used such techniques as introducing so-called interfering RNA (iRNA) to knockout certain areas of the organism’s genome, adding transgenes and gene mapping.  In casting a wide net they have incorporated proteomics – the analysis of cellular protein products, transcriptomics – the analysis of all RNAs within the cell and metabolomics – an analysis of cellular metabolic pathways- in their studies.

As a result of this exhaustive analysis, they have discovered that the organisms within this high longevity mutant population lack the enzyme PI3 kinase catalytic subunit (PI3K_cs)_.   This enzyme catalyzes the phosphorylation of Phosphatidylinositol 4, 5-bisphosphate (PIP2) to Phosphatidylinositol 3, 4, 5-triphosphate (PIP3)_.   PIP3 resides within the cell membrane and plays a critical role in cell division.  This lack of such a key enzyme is a result of the introduction of a so-called “stop gene” within the gene responsible for the production of PIP3.  As a result of this mutation, the organism produces immature oocytes and is effectively sterile.

The question that immediately arises from this data – how can the loss of such a critical enzyme result in enhanced longevity?  The answer seems to lie in the fact that PI3K is a key component in the Insulin – IGF-1 signaling pathway that is involved in many functions that are necessary for metabolism, growth, and fertility in animal models like C. elegans and also within humans.  The disruption of the insulin -IGF-1 signaling pathway in the C. elegans longevity mutant apparently increases lifespan significantly.  One apparent explanation for this seeming paradox is that the price the organism pays for reproductive success is a diminishment of lifespan.  While this relationship between longevity and the insulin -IGF-1 signaling pathway is evidenced in C. elegans, mammals with an analogous defect are, in fact, at risk for age-related diseases and increased mortality.  This difference in effect probably relates to the more complex metabolic machinery resident in a mammal versus a small invertebrate such as C. elegans.

However, within humans and other animal models, increased longevity has been associated with the nutritional state of the organism – over nutrition apparently shifts cellular metabolism in such a way as to lead to the over production of free radicals and other metabolic byproducts that are toxic to cells and a nutritional state that meets but does not exceed the individual’s nutritional requirements enhances longevity.

Although these studies focus on very specific aspects of the longevity of organisms, they do make important inroads into the overall understanding of the biological mechanisms involved in prolonging lifespan.