Addressing Obesity in a Different Way

Antoaneta Sawyer, PhD 

One of the main focuses for quite number of years of mine was on obesity and insulin resistance, at the background of the "metabolic syndrome" phenomena. This was in the early 1980s when I finished my MD degree, and started to work as an endocrinologist in one of the main hospitals in the city where I was born. As a medical student, I have been always interested in understanding all hidden biochemical and molecular mechanisms behind obesity as a phase of metabolic syndrome appearance.

Known as a quintessential nerd, I already knew enough about obesity, metabolic syndrome and Type 1 and Type 2 diabetes, as I have already cured allot of patients with the above disease and read most of the books on the syndrome. Thus, I started to specialize in endocrinology disorders. The medical team I worked for had made quite many efforts investigating what exactly where the causes of obesity and the main promoter for the future syndrome appearance or vice versa. The focus of ours was at first on identifying the bacterial and viral etiology of the obesity. At the same time most of the world famous researchers consider insulin resistance as the main cause behind obesity and started to look for auto-antibodies or mutations in genes and insulin receptors. It was extrapolated that these antibodies will bind to the insulin receptor and consequently will block them. 

One of the major clinical features of metabolic syndrome is the so called abdominal (or visceral) obesity. Obesity sets the stage for the metabolic syndrome which then itself increases one's chances of diabetes, heart disease, stroke and other maladies. Therefore, everyone in our society should be concerned about obesity as well as our government must take care on developing preventive programs. Of course they are people and people. Those in whom the disorder is quite severe will accumulate fat extremely quickly, when those in whom it is moderate - will gradually increase in weight and those in whom it is mild- may be able to keep their excess weight stationary for long periods.

Despite of the aggressiveness in weight loss programs and plans, based on restrictive diets, multiple drug treatment strategies, active exercise, sauna and massage techniques, the result seems temporary and very unsatisfactory. The pounds seem to come back immediately, after months and even years or as soon as the treatment programs are forgotten or relaxed.  BMI is a measure of how much weight anyone carries for a given height. Basically one is considered "overweight" when their body mass index is greater than the upper range of the normal ranges. In order to meet the criterion for frank "obesity" one's BMI needs to be 30 or higher. The entity known as "morbid obesity" also known as clinically severe obesity, is defined as a BMI of greater than or equal to 40. However, one can also be labeled as morbidly obese if body mass index is 35 or higher and the individual has one or more "co morbid" conditions. The following co-morbid conditions can be formulated as metabolic syndrome (diabetes, high blood pressure, high cholesterol, stroke and cardiovascular disease). Being overweight is, alongside diabetes, a leading cause of increased cholesterol levels, high blood pressure and coronary artery disease. Hence, obesity increases chances of developing all the above risk factors.

One of the missing links in the pathogenesis of metabolic syndrome is the long time unrecognized hepatic insulin resistance that appears to mediate the glucose intolerance, hyperglycemia, high level of triglyceride, and HDL-cholesterol abnormalities that contribute to the constellation of heart-disease risk factors called metabolic syndrome and it does represent a newly discovered pathophysiology link in CVD development (Biddinger et al., 2008). 

Kahn (2005) proved that insulin resistance is related to dyslipidemia, and insulin resistance- to glucose intolerance, while is not related to obesity. Actually, it is already known that obesity causes insulin resistance, but is not related to high blood pressure. Except insulin there are few other hormones involved in the etiology and pathogenesis of metabolic syndrome. One of them is the hormone- leptin. Leptin is a hormone that works as natural appetite suppressant secreted by fat cells in the body. Its discovery in the 1990s helped researchers to start experimenting with leptin that caused mice to eat less and lose weight while this rarely happens in humans. Falling levels of this hormone, that helps the brain resist tempting foods, may explain why people who lose weight often have a hard time keeping it off.

Restoring leptin to its “pre-diet” levels may reverse this problem, concluded Rosenbaum, offering a new way for dieters to finally win the weight battle. "When you lose weight you've created about the perfect storm for regaining weight," as per Rosenbaum of Columbia University Medical Center in New York, whose research appears in the Journal of Clinical Investigation. After weight loss according to the author, "the metabolism not only becomes more efficient, so the body needs fewer calories, but the brain becomes more vulnerable to tasty-looking treats. "Areas of the brain involved in telling not to eat seem to be less active. You are more responsive to food and you are less in control of it," as Rosenbaum stated.

Since then researchers started to look for the best way to use the hormones to help treat obesity. In several earlier studies, researchers found out that when people lose weight, leptin levels decrease as the body tries to protect its proper stored energy. Rosenbaum was interested to investigate the impact of this loss of leptin on the brains of people who had lost weight, and whether replacing the hormone might help them keep off the weight. He used an imaging technique known as functional magnetic resonance imaging that shows activity in the brain. The researcher studied six obese patients before and after going on a hospital-supervised diet that reduced their body weight by 10 percent. People were shown pictures of food and non-food items. The author found that after weight loss, areas in the brain responsible for regulating food intake were less active when people were shown food images, while areas in the brain responsible for emotion were more active. When the researchers restored leptin to the levels before dieting, these changes were largely reversed.

Similar results have been seen in people with a rare genetic condition in which their bodies do not make leptin. Rosenbaum believed leptin could be useful tool in helping people maintain weight loss. According to him the idea was to create a whole new class of therapies to help people with obesity keep weight off after they have lost it. Making the situation worse, insulin also co-promotes the formations of an additional third type of an adipose tissue. It seems that the more insulin the pancreas secretes, the more likely is the appearance of the “apple shape” around the waist.

Apparently hyperinsulinemia (too much insulin in the blood) can make anyone fat. And in fact insulin is the hormone that makes us fat and preliminary aged, despite we need it for energy supply. An even more insidious reason for this is that the fat cells do not develop insulin resistance to the degree other body cells do. The final result is that, in insulin resistance, all muscles and organs are being starved while the fat cells are being fed. Already knowing that adipose tissue also produces increased levels of pro-inflammatory signaling factors (eicosanoids and interleukins) cellular substances – hormones and other bioactive substances referred to as adipocytokines (Hotamisligil, 2004), as a vicious circle of all of these factors insulin sensitivity in organs like muscle and liver is decreasing (Matsuzawa, 2004). It is also highly hypothesized that secondary factors as for example: nonesterified fatty acid liberation and adipokine (e.g., adiponectin) production (Carr et al., 2004), independent of obesity and other risk factors (Egan, Greene, & Goodfriend, 2001; Janssen, Katzmarzyk & Ross, 2002) may also play a significant role in the metabolic syndrome pathogenesis. Obviously the conglomeration or the convergence of these risk factors elevates the risk for this disease (Pladevall at al., 2006). 

As it is already cited in the literature- adipokines are a variety of proteins with signaling properties produced in body fat cells. While in the past white adipose tissue (one type of body fat) used to be regarded as a passive energy warehouse which is also used to provide a buffer and protection to all internal organs, lately this concept has been turned 180 degrees up and it is now understood that white adipose tissue is highly active and dynamic metabolic organ being involved in a multitude of physiological and metabolic biochemical reactions and processes. 

Research also suggest that appetite-regulating hormones are affected by sleep and that sleep deprivation could lead to weight gain. In two separate well randomized studies, people who slept five hours or less had higher levels of ghrelin - a hormone that stimulates hunger - and lower levels of the appetite-suppressing hormone leptin than those who slept eight hours per night.  Prof. Cappuccio of the University of Warwick has proved that short sleep duration may also lead to obesity, through an increase of appetite via hormonal changes. Lack of sleep produces secretion of ghrelin, which stimulates appetite and creates less leptin, which suppresses appetite. The hormonal relationship and obesity is shown also in the HERS study published in JAMA (2000). The hyperinsulinemia in women has been shown in this study to stimulate the release of testosterone from the ovaries. It is a well known fact that people who are obese are suffering from this disorder regardless of whether they eat normally, excessively, or less than normal. At the same moment it is quite obvious that there are people who are constantly overeating but are free of the above disorder. It is easy to conclude that obesity in all its multiple forms is due to an abnormal damage in the hypothalamic area of the brain- a center that is the main regulatory mechanism of a hunger, thirst and the sexual desire.