Posts Tagged ‘leptin’

Rose Frisch, Pioneer in body fat research, passes away

February 14th, 2015

Rose Frisch, a pioneering researcher on body fat and reproduction has died. A New York Times obituary pays tribute to her contribution which laid the theoretical basis for the discovery of leptin.

 

Why the weight lost comes back

October 28th, 2011

It comes as no surprise that regaining weight after weight loss is common and frustrating to dieters. It also limits choices for policy makers who, in general, had avoided treatment strategies because of the transient nature of weight loss.

It also comes as no surprise that, after weight loss, metabolism of overweight persons slowed down and hormonal changes increased the powerful sensation of hunger. This double whammy makes maintenance of weight loss so challenging.

Now come researchers from Australia who studies a small group (only 50 overweight and obese patients without diabetes) . The group lost about 13.5kg  which led to reductions in levels of leptin, peptide YY, cholesystokinin, insulin and amylin and increases in ghrelin. There was also an increase in subjective appetite.(See Brain and Gut for background.) What is new is that these changes persisted for one year after initial weight loss. They did not revert to the levels recorded before weight loss, probably explaining why so many dieters relapse. See http://www.ncbi.nlm.nih.gov/pubmed/22029981.

Gina Kolata, writing in the New York Times, quotes Dr. Jules Hirsch as saying that researchers may just not know enough about obesity to prescribe solutions yet. “One thing is clear, he said, “A vast effort to persuade the public to change its habits just hasn’t prevented or cured obesity.” “We need more knowledge,” Dr. Hirsch said, “Condemning the public for their uncontrollable hedonism and the food industry for its inequities just doesn’t seem to be turning the tide.” Study Shows Why It’s Hard to Keep Weight Off – NYTimes.com

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.

Obesity Researchers Snag Lasker Prize

September 21st, 2010

September 21, 2010                                                                                                                                

One of the most prestigious awards in medicine has gone to two obesity researchers, Douglas Coleman and Jeffrey Friedman, for their work in discovering the hormone leptin. The discovery of leptin transformed obesity research and this prize recognizes that accomplishment. Congratulations! The Lasker Foundation – 2010 Awards

A Diet for the New Administration

September 27th, 2009

December 30, 2008

By Morgan Downey

At this time of year, millions of Americans are hoping the new Administration will solve our seemingly intractable problems at home and abroad. Millions are also hoping to lose weight in the New Year. The two are not unrelated.

Over the past three decades, obesity has increased among all segments of the population, in the United States and abroad. Obesity is now recognized as the fuel behind many major health problems from cancer to diabetes to heart disease, and a significant cause of increasing health care utilization and health care costs.

While this recognition has increased among both Republicans and Democrats (for the first time, both parties recognized obesity in their 2008 party platforms), changing public policy has not caught up with the problem. Under President George W. Bush, Medicare did undo its policy that obesity was not a disease and did expand coverage of surgery for the treatment of obesity. There have been modest increases in the research and prevention budgets at the National Institutes of Health and the Centers for Disease Control and Prevention. But by and large, the efforts of the last eight years have been largely educational: tell people they should lose weight, eat more nutritiously, and exercise more.

Duh! We get it. And it doesn’t work. Frankly, other than bariatric surgery, nothing works very well to lose significant amounts for a long period of time. There simply is not one ‘fix’ that will reverse this disturbing trend.

So here is some advice to the incoming Administration. It should be noted that many appointees named so far have a solid exposure to obesity from a public policy perspective, including former Senator Tom Daschle, nominee for Secretary of Health and Human Services, Peter Orszag, named to head the Office of Management and Budget, Governor Bill Richardson, nominated for Secretary of Commerce, and Melody Barnes, incoming chief of domestic policy at the White House.

Universal health insurance is often put forward as the panacea for all ills. However, Democrats may have to learn that expanding health insurance coverage alone does not translate to a healthier population, especially if obesity continues to increase among children and adolescents. Truth be told, we do not have adequate medical interventions to affect the rates of obesity and its effects. So, if we do not know how to truly prevent obesity or create a long term treatment, what should a new Administration do? Basically, it should focus on how to create the conditions where it is more likely than not that we will find effective strategies for prevention and treatment in the future.

  1. Being a role model is not enough. It’s been noted that George Bush and Barack Obama share a passion for physical activity. Unfortunately, the habits of the chief executive do not translate to population changes. And then there is the smoking thing. Being a role model is not an excuse for inadequate policies.
  2. Make someone responsible for obesity policy development. Right now there is no one tasked at the upper levels of the U.S. Government with dealing with obesity. True, periodically the heads of different agencies give a speech, start a new website or create a new task force but little happens because so many do so little with scant coordination.
  3. Prepare to spend some money. For one of the most significant health problems in the country, the federal government spends vastly less than on obesity than other conditions. Research, prevention and treatment costs for diabetes and heart disease, to name but two, swamp comparable figures for obesity. The federal government is spending more on getting TV converters boxes in US homes than the entire NIH research budget on obesity.
  4. Do not just focus on childhood obesity. While childhood obesity is critical, remember that the population between 7 and 16 spans only 9 years out of a lifetime. Look at obesity over the lifetime and look for relevant interventions. Support childhood prevention programs but require that they have a competent evaluation method so we will know what is working and what is not.
  5. Do focus on research. Perhaps 90% of what we know about obesity has been learned since the discovery of leptin in 1994. Too many people believe that we know everything we need to know about obesity and do not need any more research. That’s not true. A great deal is known but there are many more questions than answers. Scientific credibility on issues around body weight is sorely needed. Every hour on television another weight loss program or product is hyped as being based on doctor’s advice or scientific study. What can help on both fronts is for the Administration to create a National Institute of Obesity Research at the National Institutes of Health. A new entity like this can reenergize researchers on obesity, can more closely coordinate the many disparate programs across NIH, provide leadership to other federal agencies, states and local governments and provide much needed focus on the social and economic impacts of obesity. Furthermore, a director who is articulate can help lead policymakers and the public away from harmful and dangerous products and keep a focus on developing effective interventions. The NIH bureaucracy will oppose “disease specific” research but their interests should not trump the public health needs and the best use of taxpayer dollars.
  6. As part of your health care reform package, remove the bias against drugs for weight loss in the Medicaid statute and change the exclusion of these drugs under Medicare Part D. Then have the Food and Drug Administration revisit its risk/benefit views of drugs to treat obesity. There are few fans of pharmaceutical companies in a Democratic Congress and Administration and there are even fewer who favor drugs to treat obesity. Nonetheless, there is a huge treatment gap. We have more and more effective surgical options, one over-the-counter FDA approved pill, a couple of tried medicines, commercial plans and self-help. What we do not have are the drug treatment options we have for high cholesterol, hypertension or diabetes. Recently, major pharmaceutical companies such as Merck, Pfizer, Solvay and Sanofi-Aventis have dropped or cut back on their programs to develop drugs for obesity. There are two reasons. First, insurance companies will not reimburse for most obesity treatments, including counseling, drugs and surgery. For the pharmaceutical industry, it just did not make economic sense to invest in drugs which were not going to be reimbursed. This is where leadership by Medicaid and Medicare is critical. If these programs support obesity products, private insurance may follow. This is in the government’s long term interest because insurers can avoid treating or preventing obesity knowing that the big effects, like diabetes and heart disease will not be seen until later in life, when Medicare will become the payor. Second, many involved in obesity drug development feel, rightly or wrongly, that the Food and Drug Administration is so risk-averse that they simply cannot afford the long and expensive trials necessary to meet the rising bar of safety. A National Institute of Obesity Research can help shape clinical trials needed by the FDA and speed the process along.
  7. Look to multiply your opportunities. For example, you can use the public works part of the economic stimulus package to construct new gyms in schools, sidewalks, playgrounds, green spaces and biking/walking trails to encourage more physical activity.
  8. Let the states experiment with taxes and proposals like displaying caloric content in restaurants. Vending machines, non-diet soft drinks, high-fat foods have all come under fire in recent years for contributing to the obesity epidemic. The problem is that these products still only contribute a fraction to an individual’s total caloric intake. But no one is sure that they won’t be replaced by other calories. Likewise, there will be voices to restrict food advertising to children through the federal government’s regulatory powers. Use your National Institute of Obesity Research to design evaluation studies so that there is an objective review to see if these policies will work.
  9. Take some leadership internationally. The United States has a long history of involvement in global health issues, such as HIV/AIDs. However, very little is done on the federal level to learn from other countries’ experiences and to help shape global patterns of eating and physical activity.
  10. Avoid the single fix ideas. The obesity field is full of good advice and scant evidence. Focusing on a single fix, such a TV advertising, agricultural subsidies or sweetened beverage may consume a great amount of political resources without producing the outcome you seek.

The obesity epidemic is more likely than not to continue to grow over the next four to eight years. However, the new Administration can position the United States for meaningful change if it takes its time and devotes attention to organizing the effort. With any luck, we can make future New Year’s resolutions more likely to be successful.

Downey Fact Sheet 1 – About Obesity

September 27th, 2009

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Obesity is a global epidemic and a major health concern because of its premature mortality and extensive comorbidities. Obesity is a common, complex, multifactorial disease with a high degree of heritability. Between 25 and 40% of person with obesity have a parent who is obese. There are several significant facts to bear in mind when discussing obesity:

By Julie Snider for the Downey Obesity Report

By Julie Snider for the Downey Obesity Report

Every individual inherits a certain number of fat cells or adipose tissue. Obesity requires (a) a large number of fat cells or (b) a large volume in each fat cell or (c) both. Adipose tissue continues throughout the lifespan. Weight loss, including surgically-induced weight loss, does not remove fat cells. This is why weight regain is so common. Individuals with obesity have significantly more fat cells than the non-obese, 23-65 billion compared to 37-237 billion for persons with obesity . Early onset obesity is associated with increase adipose cell number while adult obesity is associated with normal cell number. There are two phases of life in which growth of adipose cells are likely to develop: very early, within the first few years of life and between the ages of 9-13 years of age. Those who become very obese early in life are the ones who have nearly normal cell size but have the greatest increase in cell number; whereas those with onset of obesity between 9-13 have more change in cell size than cell number. Salans LB, Cushman SW, Weisman RE, Studies of human adipose tissue. Adipose cell size and number in non0bese and obese patients. J. Clin Invest. 1973 Apr’ 52(4): 929-41)

Extremely obese individuals may have four times the number of fat cells as lean counterparts. http://www.jpp.krakow.pl/journal/archive/1205_s6/pdf/5_1205_s6_article.pdf

Human food intake and energy expenditure are controlled by complex, redundant and distributed neural systems that reflect fundamental biological reaction to food supply and energy balance. The hypothalamus and caudal brainstem play a critical role. The limbic system is important for processing information regarding previous experience with food, reward and emotion. The predisposition to store considerable amounts of energy as fat for later use is now a major health risk. Brain, appetite and obesity – PubMed Results

Extensive research over the past 10 years has shown that appetite is regulated by a complex system of central and peripheral signals which interact in order to modulate the individual response to nutrient ingestion. Satiety signals include cholecystokinin, glucagon-like peptide and peptide YY which originate from the gastrointestinal tract during a meal and through the vagus nerve reach the caudal brainstem. Here the signals move to the arcuate nucleus where satiety signals are integrated with adiposity signals, namely leptin and insulin, and with several other inputs create a neural circuit which controls the individual’s response to a meal, i.e. keep eating or stop. Neuro-hormonal control of food intake: basic mecha…[J Physiol Pharmacol. 2005] – PubMed Result

Adipose tissue, rather than some inert, jello-like, substance is an active hormonal tissue, secreting many hormones which are involved in creating signals from the gut to the brain, indicating hunger or satiety. These hormones include insulin, leptin, ghrelin, PYY-33-6, adiponctin, resistin and visfatin as well as cytokines and chemokines, such as tumor necrosis factor-alpha, interleukin-6 and others. These can lead to a chronic sub-inflammatory state which plays a critical role in the development of insulin resistance, type 2 diabetes, increased risk of cardiovascular disease associated with obesity. Adipokines: the missing link between insulin resis…[Diabetes Metab. 2008] – PubMed Result

Understanding Obesity

September 26th, 2009

While body weight is made up of several components – bone, muscle, etc. when we talk about obesity we are referring to excess fat tissue, also called adipose tissue. There are two kinds of fat tissue, brown and white (like rice come to think of it). Brown tissue is mainly found in newborn babies which serves to protect babies by releasing heat. It is converted into white cells in adults. (Scientists are looking at whether white can be converted back into brown tissue and burnt off.) White adipose tissue is made up of cells called adipocytes. These contain fat made of triglycerides and other compounds. White fat cells secrete resistin, adiponectin and leptin. The average adult has 30 billion fat cells weighting about 30 pounds. Fat cells can increase in size about 4 fold before dividing and increasing the total number of fat cells present. Adipocytes also secrete estrogen which probably accounts for higher rates of some cancers in obese persons. Adipose tissue also secrete cytokines. Among the most interesting cytokines identified has been leptin, a molecule considered to send signals to the brain of satiety, i.e. the signal to the brain to stop eating.

Brain and Gut

September 26th, 2009

Frequently, when persons with obesity are depicted in the media, they are headless forms (butts and guts I call the pictures) for we think of obesity in terms of body fat accumulation. But obesity really starts in the brain with multiple signals coming from the gut. Adipose tissue itself generates hormones such as leptin and adiponectin; the GI tract generates ghrelin which signals the brain to initiate feeding . Other products which may stimulate feeding or signal time to stop feeding include leptin, insulin neuropeptide Y among others. Parts of the brain involved are the hypothalamus, the dorsal vagal complex and the reward system.

Researchers now appreciate that food acquisition, preparation, and intake are the result of a several physical signals by which the body communicates to the brain that it is hungry and needs to start feeding or full and needs to stop. MD

Brain

So, just how does the body regulate its weight? The body needs to get its weight just right. Too little nourishment and the body becomes ill and cannot reproduce. Too much also a problem. Look at the precision needed. If one ate the recommended 2,200 calories per day (and a lot eat a lot more) they would consumer 792,000 calories in a year. If they are just 1% more calories, they would add 2 pounds per year or 20 pounds over a decade of life. That’s just an extra 22 calories a day – about half a lower fat Oreo cookie. 100 extra calories a day – about 2/3 of 1 ounce of potato chips – can result in a 5-pound weight gain a year. To keep within these narrow boundaries of health body weight, our bodies have evolved a sophisticated, redundant system to gauge its body weight and when to feed and when to stop feeding.

The four parts of this system are (1) the nervous system which connects the brain, gut and adipose tissue, (2) hormones, including those made by fat cells, (3) neuropeptides which act as messengers and (4) messenger molecules in the immune system called cytokines. These molecules control body weight. The pancreas and adipose tissue make leptin, insulin, adiponectin, visfatin and resistin. The brain makes NPY, melanocortin and cocaine and amphetamine regulated transcript called CART. The stomach makes ghrelin, PYY and CCK.

The process can begin before you eat. Even the sight, smell or thought of food can trigger the “cephalic response.” This can start the production of insulin. Ghrelin increases the desire to eat. PYY can signal an end to feeding. Under stress, the sympathetic nervous system is activiated. This promotes storage of fat, decreases metabolism and promotes insulin resistance. Weight increases and metabolism slows down when this system is activated. The key hormone is insulin which is produced in the pancreas. It is designed to use carbohydrates or store them for later use.

The signals to the brain come from both the central nervous system and the peripheral nervous system Central and peripheral regulation of food intake a…[Obesity (Silver Spring). 2008] – PubMed Result

They appear to converge in the hypothalamus region of the brain.Hypothalamic control of energy balance. [Curr Drug Targets. 2004] – PubMed Result

No fewer than ten possible automatic and largely uncontrollable responses to the modern food environment have been proposed to understand why people can consume more calories than they need without their full awareness or control over their behavior Neurophysiological pathways to obesity: below awar…[Diabetes. 2008] – PubMed Result

Obese individuals appear to respond differently to food visual cues Obese adults have visual attention bias for food c…[Int J Obes (Lond). 2009] – PubMed Result

Obese and overweight persons appear to have lower brain volume Brain structure and obesity. [Hum Brain Mapp. 2009] – PubMed Result

Gut Hormones

Leptin has been identified as one of the most powerful hormones involved in appetite regulation. Appetite control and energy balance regulation in …[Int J Obes (Lond). 2009] – PubMed Result Now, newer techniques like brain imaging can be used to understand the role the brain and central nervous system play in eating behaviours.Leptin regulates striatal regions and human eating…[Science. 2007] – PubMed Result and Neuroimaging and obesity: mapping the brain respon…[Ann N Y Acad Sci. 2002] – PubMed Result

Another class of signaling substances are neuropeptides. Orexin is one of several currently of interest to scientists. Orexin/Hypocretin: a neuropeptide at the interface…[Pharmacol Rev. 2009] – PubMed Result and Orexin neuronal circuitry: role in the regulation …[Front Neuroendocrinol. 2008] – PubMed Result

Chronic stress and obesity: a new view of “comfort…[Proc Natl Acad Sci U S A. 2003] – PubMed Result

Maternal corticotropin-releasing hormone levels du…[Obesity (Silver Spring). 2006] – PubMed Result

The role of gut hormones in the regulation of body…[Mol Cell Endocrinol. 2009] – PubMed Result

Gut hormones: a weight off your mind. [J Neuroendocrinol. 2008] – PubMed Result

Gut hormones and appetite control. [Gastroenterology. 2007] – PubMed Result

Cord blood leptin and adiponectin as predictors of…[Pediatrics. 2009] – PubMed Result

The leptin/adiponectin ratio in mid-infancy correl…[J Pediatr Endocrinol Metab. 2008] – PubMed Result

As research progresses, new theories of evolutionary development are looking at Build-ups in the supply chain of the brain: on the…[Front Neuroenergetics. 2009] – PubMed Result

Ghrelin is a gut hormone which appears to be very significant and is the subject of much research.Lean Mean Fat Reducing “Ghrelin” Machine: Hypothal…[Neuropharmacology. 2009] – PubMed Result

Appetite

Viewing photographs of fattening foods, compared to non-food objects can result in greater activiation in parts of the brain. Activation in brain energy regulation and reward c…[Int J Obes (Lond). 2009] – PubMed Result In one study, obese women had greater brain activity in response to pictures of high fat foods than did non-obese women. Widespread reward-system activation in obese women…[Neuroimage. 2008] – PubMed Result and Effective connectivity of a reward network in obes…[Brain Res Bull. 2009] – PubMed Result

Gut peptides and the regulation of appetite. [Obes Rev. 2006] – PubMed Result