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.
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
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.
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.
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:
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
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.
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
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
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
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
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