Posts Tagged ‘hormones’

Hunger, Prader-Willi Sydrome and differences between the brains of persons at normal weight and with obesity

January 15th, 2014

A New York Times report today by Andrew Pollock details the efforts of researchers and drug companies to unravel the mysteries of Prader-Willi Syndrome. Prader-Willi Syndrome is marked by insatiable appetite and obesity. Patients often slow metabolisms, intellectual difficulties and autistic behavior. (For more information see the Prader-Willi Syndrome Association website.) The condition is known to be caused by missing segments on chromosome 15. While Prader-Willi is a genetic disease, it is not necessarily found in families. 70% of cases are due to a deletion in chromosome 15 from the father; deletion from the maternal side is responsible for about 20%.  This is known as genomic imprinting where the gene turns on or off depending on which parent contributes it.

Drug developers Ferring Pharmaceuticals, Rhythm, Arena Pharmaceuticals (which sells Belviq, an FDA approved drug for weight loss) and Zafgen are looking at drugs for the condition. Zafgen is releasing results of a small clinical trial today.

While Prader-Willi is a rare condition and is well-understood regarding its genetic cause, research on the syndrome is helping to open up research on the fundamental aspects of hunger.

One of the great gaps in public and policy-makers understanding of obesity is the role of hunger, driven by powerful networks within our bodies. Hunger is clearly one of the most powerful of human emotional states as it involves existential survival, much like the inability to breathe or drowning. In my experience, many persons with obesity report nearly constant states of hunger which our food-laden environment is almost universally able to slake. But reports from individuals are a poor substitute for research. Now, in the past decade, science has filled in the gaps.

After a meal, appetite is suppressed; after energy expenditure hunger is increased. Those sensations, satiety and hunger, are caused by changes in nutrients and hormones, including PYY, GLP-1, ghrelin, leptin and insulin circulating in the body. In normal physiology, the hypothalamus balances the food intake with the metabolic requirements. This system works, usually, with great precision. This appetite process is called homeostatic. Non-homeostatic food control is driven by sight, smell, taste, habits, emotional and economic influences. The brains areas involved in nonhomeostatic food control include the hippocampus, the amygdala, insula, striatum and orbitofrontal cortex. The two systems are not independent but highly integrated.

Recent research points to understanding that higher food intake in persons with obesity is due, probably in substantial part, to differences in how the brains of  persons with obesity respond to food cues compared to  persons at “normal” weights.

Researchers using techniques such as functional Magnetic Resonance Imaging (fMRI) are mapping the physiological networks of hunger and are understanding  why we get hungry and why maintaining weight loss is so hard. FMRI allows scientists to locate specific areas of the brain which show responses to specific stimuli. Thus they can compare obese and lean subjects in different conditions. (For an explanation of the use of fMRI studies in appetite regulation see this article from de Silva and colleagues and from which this illustration is taken.

Using fMRI, researchers at Emory University have identified areas in the brain identified with taste and the reward system that ‘light up’ when subjects just looked at pictures of appetizing food.  Meanwhile, other researchers, also using fMRI, found different reactions to pictures of high-calorie foods between men and women. When healthy subjects were given injections of ghrelin, fMRI scans showed increased brain activity in response to pictures of food and were correlated with self-reported hunger ratings. (Ghrelin is a peptide hormone that stimulates hunger and food consumption.) Just in October, a study was published showing that images of high fat foods produced stimulation of the brain’s reward network in Hispanic females.

It isn’t only pictures of food which tweak the brain. Subjects with obesity differed from lean subjects in which area of the brain responded to food aromas. The brain areas affected by food aromas are similar to those affected by addictive substances, like alcohol.

In short, individuals prone to weight gain and obesity have altered neuronal responses to food cues in brain regions known to be important in energy intake regulation and these differ from lean person’s responses.

Of great concern is when such differences occur? A study from the University of Kansas Medical Center used fMRI on children and adolescents, ages 10-16, half at a healthy weight and half with obesity. They found the obese group showed greater activation to food pictures both before and after a meal than the healthy weight group. Unlike the healthy weight group, the obese group’s response to food stimuli did not diminish significantly after eating. The authors concluded, “This study provides initial evidence that obesity, even among children, is associated with abnormalities in the neural networks involved in food motivation, and the origins of neural circuitry dysfunction associated with obesity may begin in early life.”

This understanding of obesity has great implications for the prevention and treatment of obesity and for the establishment of effective public policies.

What’s Wrong with a Little Fat-Bashing?

October 3rd, 2011

So what actually is wrong with fat-bashing? Everyone does it. Isn’t it a good thing to embarrass and ridicule people into healthy behavior? Well, yes. I guess. If it worked. The round of vitriol directed at Chris Christie for his weight is nothing which millions of persons with obesity haven’t experienced in their own families or workplaces or just walking down the street. The problem with telling a person with obesity to eat a salad and take a walk ,like the Washington Post’s Eugene Robinson did, is like telling a person with Parkinson’s disease to just stop shaking or a drug addict to just say no. It ignores the complexity of disease focusing only on the visible end point of a long and complex biological and social process.  

Given the context of the fat-bashing regarding New Jersey Governor Chris Christie, it is useful to revisit Dr. Jeffrey Friedman’s 2003 commentary, “Make War on Obesity, not the Obese.”  

Jeffrey Friedman and Douglas Coleman’s names came up this weekend as possible contenders for the Nobel Prize in Medicine. (They would have my vote if I had a vote) for their work in the discovery of leptin in 1994. Their work  revolutionized obesity research, showing how a hormone produced by fat tissue plays a key role in body weight regulation. 

Friedman’s commentary is still timely and deserves revisiting while obesity, especially extreme or severe obesity, is in the news. I think it remains one of the best scientific explanations of obesity and should give pause to anyone who wants to throw a stone or two.

 His major points are:

 

  1. “There can be no meaningful discussion of obesity until we resist the impulse to assign blame.  Nor can we hold to the simple belief that with willpower alone, one can consciously resist the allure of food and precisely control one’s weight.“

  2. The facts are these “(i) the increasing incidence of obesity in the population is not reflected by a proportionate increase in weight; (ii) the drive to eat is to a large extent hardwired, and differences in weight are genetically determined;  and (iii) obesity can be a good thing depending on the environment in which one (or one’s ancestors) finds oneself.”

  3. The change in weight attributable to any recent changes in diet or a more sedentary life-style is much smaller than the enormous differences in weight, often numbering in the hundreds of pounds, that can be observed among individuals living in today’s world.”

  4. “Twin studies, adoption studies, and studies of familial aggregation confirm a major contribution of genes to the development of obesity. Indeed, the heritability of obesity is equivalent to that of height and exceeds that of many disorders for which a genetic basis is generally accepted. It is worth noting that height has also increased significantly in Western countries in the 20th Century.”

  5. “In general, obesity genes encode the molecular components of the physiologic system that regulates energy balance. This system precisely matches energy intake (food) to energy expenditure to maintain constant energy stores, principally fat. That there must be a system balancing food intake and energy expenditure is suggested by the following analysis. Over the course of a decade, a typical persons consumes approximately 10 million calories, generally with only a modest change in weight. To accomplish this, food intake must precisely match energy output within 0.17% over that decade. This extraordinary level of precision exceeds by several orders of magnitude the ability of nutritionists to count calories and suggests that conscious factors alone are incapable of precisely regulating caloric intake.”

  6.  “Feeding is a complex motivational behavior, meaning that many factors influence the likelihood that the behavior will be initiated. These factors include the unconscious urge to eat that is regulated by leptin and other hormones, the conscious desire to eat less (or more), sensory factors such as smell or taste, emotional state, and others. The greater the weight loss, the greater the hunger and, sooner or later for most dieters, a primal hunger trumps the conscious desire to be thin.”

  7.  The increase in weight is not evenly distributed in the population. “In modern times, some individuals have manifested a much greater increase of BMI than others, strongly suggesting the possibility that in our population (species) there is a subgroup that is genetically susceptible to obesity and a different subgroup that is relatively resistant.”

  8.  “Obesity is not a personal failing. In trying to lose weight, the obese are fighting a difficult battle. It is a battle against biology, a battle that only the intrepid take on and one in which only a few prevail.” A war on obesity, not the obese. [Science. 2003] – PubMed – NCBI.