The Relationship between Obesity and Insulin Resistance

Metabolism – the sum of all the chemical reactions in the body necessary for sustaining life - and immunity – the ability of the organism to defend against threats posed by the invasion of microorganisms such as bacteria and viruses – are intimately linked in the biology of mammals. It is this relationship that allows the organism to adapt to changes in both the internal and external environments. However, within the modern western diet and lifestyle that promotes the development of obesity, this close association of metabolism and immunity can have deleterious consequences. Through the evolutionary history of the human species, humanity has had to survive in the face of the possibility of death as a result of starvation, infection and predation. It is only relatively recently in human societal development that such threats have been significantly lessened due to the introduction of agriculture to meet the nutritional needs of human populations and significant progress in technology and medicine. These age-old threats have been supplanted, however, by new concerns regarding individual mortality posed by cardiovascular disease, diabetes and cancer. The evidence now strongly indicates that obesity is an essential component of these troubling diseases. Between 1980 and 2008, the total number of obese individuals has essentially doubled worldwide to .5 billion individuals and the global death rate attributed to obesity is currently at ~ 3 million people per year. Drs. Justin Odegaard and Ajay Chawla from the Cardiovascular Research Institute at the University of California at San Francisco have examined the “cellular and molecular connections between chronic low-grade inflammation, insulin resistance and obesity-induced metabolic disease.” The focus for this report will be on the relationship between obesity and insulin resistance. Within this context, obesity can be defined as an imbalance between caloric intake and energy expenditure – calories in/calories out. This state of imbalance leads to the storage of excess nutrients in white adipose tissue (WAT). For lean individuals this imbalance is readily compensated by metabolic adjustments in WAT, liver and skeletal muscles. However, in a state of chronic over-nutrition, these pathways are overwhelmed leading to wide-ranging intracellular and extracellular dysfunction. Although these deleterious effects are the result of complex metabolic processes, the end product of these disturbances leads to the inhibition of insulin signaling – insulin resistance - through the modification of the insulin receptor substrate resulting in diabetes. In addition, the metabolic stress responses that are a product of chronic obesity, leads to the triggering of the innate immune receptors resulting in inflammation. This is, indeed, troubling data especially in regards to global public health. It appears that chronic over-nutrition is a cause for concern since the health ramifications that result from obesity have a major impact on individual quality of life and mortality.

Genetic Mutations Associated with Human Melanoma

As we have described in previous articles, there is a strong association between cancer and genetic mutations that disrupt the normal constraints placed upon cell growth and division.  In this article, evidence will be presented that links a particular set of unusual genetic mutations with human melanoma. 

Melanoma is a particularly deadly cancer of the skin.  The cells that become cancerous in melanoma are the so-called melanocytes that elaborate melanin – the pigment responsible for skin color.  The precise etiology of melanoma is not known; however, exposure to ultraviolet (UV) radiation either from natural sunlight or derived artificially from tanning beds increases the risk of developing this cancer.  The particular danger inherent in melanoma is the propensity of cancerous cells to travel from the initial site of development to other tissues of the body – a process referred to as metastasis.  It is therefore important to detect the presence of the cancerous mass before it has the opportunity to spread.

The research to date has revealed that most genetic mutations associated with various cancers seem to reside within the protein-coding regions of genes or at the splice junctions.  However Dr. Franklin W. Huang and his colleagues at the Broad Institute of Harvard and MIT, Cambridge MA were interested in determining whether any mutations consistent with tumor production appeared outside of the protein-coding regions.

To arrive at an answer to this question, the investigators performed an exhaustive analysis of whole-genome sequencing data from 70 individual cancerous melanomas.  From this analysis they discovered two independent mutations that reside within the promoter region – the promoter region of the genome lies outside of the protein coding region of the genes and is responsible for the initiation of gene transcription – for that region of the genome responsible for the production of the telemorase reverse transcriptase enzyme (TERT).  These mutations were found in 71% of the melanomas examined – this represents a remarkably high association.    In addition, they found an elevated frequency of these mutations in human bladder and liver cancer cells grown in culture.  TERT is of particular significance because this enzyme is responsible for lengthening telomeres in DNA strands and promoting cells to grow out of control.  It would, therefore, be a reasonable candidate for the mechanism of tumorigenesis. 

Single Nucleotide Polymorphisms and Intestinal Cancer

The complete sequencing of the human genome has revolutionized the study of human biology especially in relation to the understanding of the etiology of cancer.  This has been made possible by the fact that data can be accumulated from the DNA of cancer patients and studied to determine if there are any underlying patterns in regards to genetic anomalies that correlate with the different types of cancers.  Cancer results from a particular cell type growing out of control of the usual biological restraints placed upon such growth.  Cancer can arise from any tissue in the human body. 

For many years it has been known that there are certain genes that correlate with cancer development; these genes are referred to as oncogenes.  One such oncogene is referred to as myc found on human chromosome 8 (there are 23 chromosome pairs that make up the human genome – 22 pairs are so-called somatic chromosomes and 1 pair is the sex chromosomes).  It has been clearly shown that the activated product of the deregulated myc oncogene interferes with controlled cell growth and apoptosis – programmed cell death.  The net effect of these actions is uncontrolled cell growth and ultimately carcinogenesis.  Furthermore, single nucleotide polymorphisms (SNPs) – SNPs are alterations in genetic structure that represent a change in a single nucleotide – have been found upstream from the myc gene that strongly correlate with increased incidences  of different types of human cancer, including cancers of the breast, bladder and prostate.

The hypothetical causal relationship of the existence of myc-related SNPs to cancer has been extremely difficult to unambiguously confirm.  For this reason, Dr. Inderpreet Kaur Sur and his colleagues at the Science for Life Center at the Department of Biosciences and Nutrition, Karolinska Institutet in Stockholm, Sweden studied in detail the relationship between SNPs associated with the myc oncogene and intestinal tumors using the mouse model.  For the purposes of this study, the team generated mice deficient in a myc regulatory element called rs6983267.  This element is, in fact, a known SNP that is associated with more human cancer-related deaths than any other studied genetic mutation.

In addition, the investigators discovered that myc transcripts – mRNAs generated from the myc gene locus - were expressed in the intestinal crypts indicating that the myc gene was active in these genetically modified mice but at lower levels.  Most importantly, these mice proved to be remarkably resistant to the expression of intestinal tumors even when they were crossed with mice possessing the APCmin mutation – a mutation known to cause spontaneous intestinal tumors.

These results are extremely important.  They confirm the relationship between a particular SNP associated with the myc oncogene and tumorigenesis.  Although these results were obtained using the mouse as the model organism, for obvious reasons, the SNP studied has been well-established in human cancers.  Furthermore, these results show the immense benefits now being realized from the exhaustive study of the human genome; for, the etiology of cancer has been strongly linked to genetic anomalies.

The Role of Platelets in Defense against Malaria

Platelets are normal constituents of the blood.  They play a fundamental role in blood clotting, but have been shown to play other more diverse functions.  For example, it has been well established that platelets impede the growth of the malaria parasite, Plasmodium falciparum.  The malaria parasite enters the bloodstream following the bite of its carrier, the female anopheles mosquito.  Once circulating in the bloodstream, the parasite preferentially invades circulating red blood cells.  Platelets bind to parasitized cells and kill the parasites within.  This has been amply demonstrated in studies with mice – normally resistant to infection – that have been purposefully depleted of platelets.  These mice invariably die of infection.  It has also been shown, that this property of platelets is independent of species – platelets derived from mice or humans exert the same effect in either host.  In addition, platelets seemed to bind to both infected and non-infected cells, but have a marked preference for infected red cells. 

Although this capability of platelets has been well established, the actual molecular mechanism underlying this function has not been fully demonstrated.  Dr. Brendan J. McMorran and his colleagues from the Australian School of Advanced Medicine in Macquarie University, Sydney Australia and the Menzies Research Institute Tasmania University, Hobart, Australia have made a significant contribution to the understanding of the mechanism involved.

From their work, they have shown that platelet factor 4 (PF4) together with the Duffy-antigen receptor (Fy) are necessary for the platelet-mediated eradication of the Plasmodium falciparum parasite.  Furthermore, they have shown that upon the binding of platelets to the parasitized red blood cell, PF4 is released and that it is this protein that is responsible for the killing of the parasites residing within the infected red blood cells.  In order for PF4 to exert its effect, Fy needs to be present; it is Fy that selectively binds to PF4.  It has also been shown that those individuals that have a genetic anomaly that undermines the expression of Fy are devoid of the protection against the parasite provided by platelets.

These findings help to elucidate the role that platelets play in the defense against parasitic infections.  Uncovering the underlying mechanism for such a defense may prove to be invaluable in combating malaria - a disease that has a devastating impact on a significant portion of the world’s population.    

DNA Supercoils

The structure of DNA is ordinarily represented as a double helix.  In fact, functional DNA found within cells has an additional level of complexity – the double helix also twists upon itself resulting in “extended intertwined loops” called plectonemes.  Since it is well established that there is close and necessary relationship between structure and function in the biological realm, it is of immense scientific interest to understand the dynamics of this supercoiling property.

DNA, of course, possesses the blueprint upon which life is based – it contains the information that is used to construct the structural and enzymatic proteins that are essential for life.  In order to fulfill its role successfully, the genomic processes depend upon exquisite and precise mechanisms to control the expression of genes.  Furthermore, since the complex structure of DNA involving supercoils plays a pivotal role in these control mechanisms, it would be of interest to understand the dynamics of the individual plectonemes.

Current understanding of supercoiling suggests that this phenomenon is caused by the movement of proteins along the path of the DNA molecule.  This movement produces perturbations in the DNA structure causing the DNA to twist or writhe- the coiling of the DNA around itself.  The overall impact of these conformational changes induces both local and global effects.

A locally-derived distortion or destabilization of the DNA can alter transcription – the process by which the information contained in genes is transcribed to messenger RNA (m-RNA) – or induce binding to the DNA.  A global change in the overall conformation of DNA can bring distant sections of the DNA together resulting in genetic recombination.

Heretofore, it has proved to be an immense technological problem to study the actual dynamics of supercoiling since analysis has relied, almost exclusively, upon static imaging.  Dr. M.T.J. van Loenhout and his colleagues from the Delft University of Technology, Department of Bionanoscience, Kavti Institute of Nanoscience in Delft Netherlands have overcome this obstacle by designing what they refer to as, “single-molecule magnetic tweezers.”  With this new analytical tool, they have been able to study the real-time dynamics of individual plectonemes.

Van Loenhout and his co-workers have found that plectonemes move along the DNA by simple diffusion or what they refer to as, “fast hopping” that enables long range plectoneme displacement.  These conclusions as to the nature of the supercoiling of DNA are extremely important for they help elucidate the dynamics of a process that is fundamental to the nature of DNA within living cells. 

Chronic Myeloid Leukemia (CML) and a Remarkable Drug to Treat It.

Chronic Myeloid Leukemia impacts approximately 5000 people a year.  It is characterized by the uncontrolled growth of a subset of circulating white blood cells (WBC).  The onset of this disease correlates with a particular genetic abnormality that has been well categorized.  The change in the genetic material is demonstrated by the appearance of the so-called “Philadelphia” chromosome.  This chromosome results from the anomalous exchange of genes between chromosome 9 and chromosome 22 – the human genome possesses 23 pairs of chromosomes one pair of which contains the genes that determine human gender XX (female) and XY (male).  This genetic rearrangement results in the juxtaposition of two genes namely, BCR and ABL.  The resulting gene combination, BCR-ABL is responsible for the production of a novel gene product that contributes to uncontrolled cell growth i.e. CML.

The realization of this mechanism opened the possibility that if the activity of the deleterious protein product could be curtailed, a cure of CML could be envisioned.  This particular approach is known as molecular targeting, for it targets a particular molecular substance known to play a critical role in the development of disease – in this case, CML.

When it became clear that the “offending” protein was a member of a class of proteins referred to as kinase enzymes, Drs. Zimmerman and Buchdunger tested a plethora of possible drug candidates to see what compound could precisely target this enzyme without adversely affecting any other cellular processes.  Their work proved rewarding; they ultimately discovered the efficacy of a drug given the name, Gleevec (imatinib).

The results have been very impressive.  As reported in the Journal of the National Cancer Institute (JNCI), CML patients who have been treated with Gleevec have gone into complete remission after two years of treatment and have been shown to have survival rates similar to the general population.  According to a statement released by the journal, “This study offers the first evidence that a disseminated cancer, not amenable to surgery, can be controlled to the point of giving patients a normal life expectancy.”

These results are extraordinary, yet they point to the efficacy of the molecular targeting approach.  This methodology may prove applicable to other heretofore treatment-resistant diseases. 

Stimulants, Opiates and the Human Brain

Chemical stimulants such as cocaine and opiates such as morphine profoundly influence behavior through their interaction with and alteration of brain chemistry.  Members of the opiate family of compounds are known to markedly reduce the experience of pain.  Of particular interest in this regard is the neurotrophic factor, BDNF – a direct product of brain chemistry.  BDNF plays a very important role in maintaining so-called “neural plasticity.”  This plasticity represents an intrinsic ability of the human brain to alter neuronal pathways and synapses – the junctions between nerve cells that allow the passage of electrical signals through the nervous system – in response to changes in behavior and the environment especially in regard to bodily injury.  This is a highly adaptive function of the brain that is often seen in the victims of stroke – allowing individuals to compensate for brain damage.

BDNF has been shown to play a key role in the kind of neural and behavioral plasticity that is induced by the use of cocaine and other stimulants.  Furthermore, it has been demonstrated that the mode of action of BDNF in this regard is intimately connected with the mesolimbic dopamine (DA) system that represents a key reward circuit in the brain.  Dopamine is one of major neurotransmitters in the brain that is involved in many diverse brain functions.  It is the irreversible loss of dopamine-producing cells that results in the symptoms associated with Parkinson’s disease.  The net result of the interaction of BDNF with DA system is the promotion of further actions of stimulant drugs.

Dr. Ja Wook Koo and his colleagues at the Fishberg Department of Neuroscience and Friedman Brain Institute at the Mount Sinai School of Medicine in New York have implicated BDNF in the mode of action of the opiate drug, morphine and have helped elucidate the mechanism through which it works.  In contrast to stimulants, opiates exert their effect on the brain through the promotion of DA signaling by the inhibition of ϒ-aminobutyric acid (GABA) – an important neurotransmitter in the brain that plays a role in regulating neuronal excitability through an inhibitory pathway.  The investigators have clearly shown that BDNF is, in fact, a negative modulator of morphine action.

This is an important finding in that is helps elucidate the mechanisms involved  with  brain-associated adaptations within the reward circuitry that occur with the use of morphine – a drug that is widely used to treat severe chronic pain especially at the end of life.