Is obesity jab 'two years away'?

reposted from: http://www.nhs.uk/news/2014/06June/Pages/Claim-that-obesity-jab-is-two-years-away-premature.aspx

crabsallover highlights, key points, comments / links.

“New obesity jab could be available within two years,” the Mail Online reports. The headline comes following news that scientists have identified a protein that may help stimulate the production of brown fat.

Brown fat helps keep mammals warm. In humans, it is mostly found in newborn babies, who are particularly vulnerable to cold. As we age, we do not need brown fat as much, and in adulthood we have mostly white fat. Excess white fat (obesity) can damage your health, whereas brown fat has been linked to protection against obesity and type II diabetes; as such, it has attracted increasing interest and research.

Brown fat also helps to burn calories when the body is exercising (or, less pleasantly, when you are cold enough to shiver). Unlike white fat, it acts like muscle, keeping the body firm and toned.

The study, which involved mice rather than people, found that the new protein helped stimulate the production of brown fat. 

The optimism surrounding these findings is based on the hope that researchers could potentially harness the effects of this molecule to develop an obesity treatment in the future.

However, claims that an “obesity jab could be available within two years” seem overly optimistic.

Studies on people are needed before any claims of this kind can be made.

Where did the story come from?

The study was carried out by researchers from Harvard Medical School and the Dana-Farber Cancer Institute, in the U.S., and was funded by grants from the US National Institutes of Health and JPB Foundation.

The study was published in the peer-reviewed science journal Cell.

The Mail Online’s headline that “a new obesity job could be available within two years” is not supported by the publication, although the authors did state that the “therapeutic potential in metabolic diseases is obvious”. 

There was a related study, performed by the same research team, in which the effects of the hormone irisin were studied, also in mice. Evidence suggests that irisin can also help stimulate production, by turning white fat into brown fat.

Somewhat confusingly, the Mail Online and the Daily Express seem to have reported on the findings of both studies as if they were a single piece of research.

What kind of research was this?

This was a laboratory study that used mice to identify and investigate the function of hormones released in muscles in response to exercise and cold.

Obesity levels in middle- and high-income countries is high and continuing to rise, with associated diseases including type 2 diabetes, cardiovascular disease and cancer.

As a result, the authors state there is increasing interest in brown fat – which uses energy to create heat and stops mammals becoming overly cold. In humans, brown fat is mostly found in newborn babies, who are particularly vulnerable to cold (as they have a large surface area to body volume ratio and are unable to shiver). As we age, we do not need as much brown fat to keep us warm, and have mostly white fat. However, brown fat has also been linked to protection against obesity and type II diabetes. Some hope that finding a way to make the body produce more brown fat, or convert white fat into brown fat, may help prevent obesity.

Exercising is a simple way to increase energy expenditure, and helps prevent obesity and associated metabolic disorders. It also increases the circulating levels of certain hormones released from muscle, which are known to mediate some of the beneficial effects of exercise.

The researchers wanted to see if there was the potential to harness some of these hormones to artificially mimic the beneficial effects of exercise, and investigated the role of brown fat in this process.

What did the research involve?

The research involved numerous genetic and protein studies involving mice. They were looking for molecules that were released during exercise and in response to cold, which would give them clues as to how exercise and brown fat activity were generating health benefits. By screening numerous molecules, they sought to identify those that were having the most important effects. 

What were the basic results?

• The experiments identified a molecule called meteorin-like (Metrnl) (Genecards), which was present in muscle and fat.
• Circulating levels of Metrnl rose after mice exercised and when they were exposed to the cold. 
• Metrnl was found to stimulate energy expenditure and converted regular fat into heat-producing brown fat. Metrnl also improved glucose tolerance – a sign of metabolic health – in mice fed a high-fat diet. It was doing this by interacting with many aspects of the body’s immune system and its temperature regulation systems.
• Blocking Metrnl action stopped these beneficial effects – confirmation that it was heavily involved in this process.  
• Metrnl levels increased as a result of repeated bouts of prolonged exercise, but not during short-term muscle activity.

How did the researchers interpret the results?

The researchers concluded that Metrnl’s “therapeutic potential in metabolic diseases is obvious. The recombinant Metrnl protein used here hints at that potential, but other proteins with better pharmacological properties will be required”.

Conclusion

This study identified a molecule that is induced by exercise and exposure to cold. It has been implicated in stimulating brown fat development and improving glucose tolerance – both of which have been linked to a lower risk of obesity and type II diabetes, giving hope that harnessing the effects of this molecule could create obesity treatments.

However, this optimism appears premature, as the research was conducted solely in mice. It will need to be reproduced and validated in humans to see if it is safe and effective at stimulating weight loss or other benefits. These remain unproven at this stage.

Other promised potential “anti-obesity jabs” include leptin and irisin, neither of which have delivered convincing results in human trials. This serves to highlight that when a new compound shows promise in mice, these don’t necessarily translate into effective medicines for humans.

On this basis, the Mail’s headline that a “new obesity jab could be available within two years” appears unjustified.

Rather than holding out hope of some magic medical bullet to beat or treat obesity, it’s best to try and lose weight through healthy eating and exercise. Our free 12-week NHS Weight Loss plan can help you achieve sustainable weight loss. 

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Links to the headlines

New obesity jab could be available within two years after scientists discover hormone that helps the body burn fat. Mail Online, June 6 2014

New drug boosting immune system could beat obesity and diabetes. Daily Express, June 6 2014

Links to the science

Rao RR, Long JZ, White JP, et al. Meteorin-like Is a Hormone that Regulates Immune-Adipose Interactions to Increase Beige Fat Thermogenesis. Cell. Published online June 5 2014

Study probes weight gain after diets

reposted from: http://www.nhs.uk/news/2012/04april/Pages/vlcd-weight-loss-diets-hormone-regain.aspx

crabsallover highlights, key points, comments / links.

The body seems to have a hormonal backlash after dieting so that the weight is piled back on quickly. Keep on monitoring your weight and adjust your calorie intake & exercise to maintain your desired BMI.

Study probes weight gain after diets

NHS Choices Tue Apr 24, 2012 19:00 Share

“Trying to lose weight alters your brain and hormones so you're doomed to pile it on again,” the Daily Mail reported today.

Many people struggle to maintain their new weight after a diet, and this news is based on a small study that investigated the biological reasons for this. Researchers monitored the hormone levels of 50 volunteers who were given very low calorie diets, of around 500 calories a day, for 10 weeks alongside weight loss advice, a recommended exercise programme and supervision from a dietitian. Comparing levels of several dietary hormones before, during and after the weight loss programme, researchers found that many of the hormonal changes experienced during the diet persisted a year after the diets ended, when participants were trying to maintain their new lower weight. Researchers suggest that this means the body has a hormonal “backlash” against the lack of calories during a diet, and will instruct the body to replace lost weight in the future.

This study provides some useful evidence about hormone levels and appetite in obese people following a weight loss programme. However, to make firm conclusions, larger studies are needed to compare dieting participants with people not attempting the diet. People who want to lose weight should not be alarmed by this study’s findings or feel “doomed”. It is well known that keeping off weight lost through dieting is difficult. Instead, they should see a dietitian or their GP if they are struggling to maintain or reach a healthy weight.

Where did the story come from?

The study was carried out by researchers from the University of Melbourne and La Trobe University, both in Australia. It was funded by Australia’s National Health and Medical Research Council, the Sir Edward Dunlop Medical Research Foundation and grants from the Endocrine Society of Australia and the Royal Australasian College of Physicians. The study was published in the peer-reviewed New England Journal of Medicine.

During weight loss diets, people experience changes in the levels of various appetite-regulating hormones in the body. The researchers behind this new study say it is not yet known whether these changes are sustained when people try to maintain their new lower weight.

The story was reported accurately by the Daily Mail. However, the newspaper’s announcement that people trying to lose weight are “doomed” to put it back on again seems overly negative and does not represent the findings of this small study.

What kind of research was this?

This research looked at 50 obese men and women who took part in a 10-week weight loss programme. Measurements of their weight, hormone levels and appetite were recorded before, during and one year after the programme.

The research was a case series. This is a type of descriptive study of a group of people who have something in common. For instance, they may have the same condition or are using the same treatment. This type of study describes characteristics or outcomes in a single group, but does not compare them with people who are offered a different treatment or who do not have the condition.

The researchers say that many people experience initial weight loss during a diet, but that most obese people fail to maintain their reduced weight. Understanding the biological barriers that stop people keeping off lost weight, and the hormones involved, is crucial for designing ways to prevent weight gain, they argue.

What did the research involve?

Researchers recruited 50 obese adult volunteers through a newspaper advert (34 post-menopausal women and 16 men) to undertake a 10-week weight loss programme. This programme featured a very low energy diet, which provided 500–550 calories a day. This is around a quarter of the normal intake for a woman.

A healthy body mass index is considered to be between 18.5 and 25kg/m2. In this study, the researchers recruited people with a body mass index between 27 and 40. Smokers, people with significant illness (including diabetes) and those taking medications known to affect body weight were excluded from the study.

At the end of the 10-week programme, participants received individual counselling and written advice from a dietitian on a recommended dietary intake to maintain weight loss. They were also encouraged to perform 30 minutes of moderately intense physical activity on most days of the week. Over the following year, participants visited the hospital every two months and were contacted by telephone between visits for continued counselling.

Patients were assessed for circulating levels of a variety of hormones at the start of the study, at week 10 and after the study at week 62. Subjective ratings of appetite were also measured. Measured hormones included:

• leptin – a hormone produced by fat cells and an indicator of energy stores
• peptide YY, glucagon-like peptide 1, amylin, pancreatic polypeptide, cholecystokinin and insulin – hormones released from the gastrointestinal tract and pancreas in response to food (they reduce food intake)
• ghrelin – a hormone also released in response to food, which stimulates hunger
• gastric inhibitory polypeptide – a hormone that may promote energy storage

Researchers used two types of analysis to report their findings:

• an “intention to treat” analysis that included all participants who started the study, even if they did not complete it
• a secondary analysis that included only those who completed the trial (34 participants)

The intention to treat analysis is the preferred analysis, as including only participants who completed the trial will bias the results. By including everyone who started a study, an intention to treat analysis also reveals other factors, such as the potential dropout rate for a treatment if it were used in clinical practice.

What were the basic results?

Of the 50 participants who began the study, only 34 completed it (68%). Although there were no significant differences between those who completed the study and those who did not, there was a trend towards younger participants not completing the study, which may have had some effect on the results.

At the end of the 10-week programme, the average (mean) weight loss was 13.5kg, and participants had a significant increase in subjective measures of appetite (p<0.001). Significant reductions were seen in levels of the hormones leptin, cholecystokinin, insulin and the appetite-suppressing peptide YY (P<0.001). There were also increases in levels of the appetite-stimulating hormone ghrelin (P<0.001).

One year after the end of the programme, mean weight loss since the start of the study was 7.9kg. This means that participants had put back on some of the weight initially lost, but had maintained an overall weight loss. A year after the end of the weight loss programme, there were still significant differences in the mean levels of appetite-suppressing peptide YY and the appetite-stimulating hormone ghrelin (p<0.001) compared with at the start of the study. Participant-reported hunger had also risen (p<0.001).

How did the researchers interpret the results?

The researchers concluded that after initial weight reduction in obese people, circulating levels of hormones thought to encourage post-diet weight regain do not revert to the levels seen before weight loss. One of the researchers described this as a “co-ordinated defence mechanism” with multiple components all directed towards making us put on weight. In other words, the body mounts a backlash against dieting and the reduced intake of food and energy it brings.

The researchers also said that long-term strategies to counteract this change may be needed to prevent “obesity relapse”.

Conclusion

This small study found that after obese adults completed an intense weight loss programme, the levels of several dietary hormones did not revert to their pre-diet state. Instead, during this long-term maintenance phase, certain hormone levels thought to affect appetite and weight gain remained as they were during the intense weight loss phase. This may affect a person’s ability to maintain the weigh loss benefits from their very low calorie diet plan.

The study had limitations, some of which the authors noted:

• The study featured a very low calorie diet (500–550 calories a day), recommended exercise and supervision from a dietitian. The levels of support, motivation and weight loss seen in this study may not be typical of those seen in everyday diets. In particular, this diet may not reflect the type of dieting in people hoping to lose a moderate amount of weight.
• The study recruited people with a minimum BMI of 27 and an average BMI of 35 (healthy BMI range is 18.5 to 25). Very low calorie diets are generally not considered to be suitable for people who are only slightly overweight or with a BMI just above 25. Therefore, participants in this study may not represent the types of people who would normally use these diets.
• This study did not have a control group of people who did not participate in the weight loss programme. Using a control group, though not essential for this type of study, would have allowed the researchers to make allowances for the natural fluctuations in many hormones. 
• The dropout rates were high, with only 34 people completing the study out of the original 50 who started it. This is typical for weight loss studies. The researchers say that there were no significant differences between those who did and did not complete the study, though there was a trend for younger participants to drop out. Therefore, the findings of this study may not be useful for a younger obese population.
• The authors mainly analysed results for only the people who completed the study. It is not known whether changes in hormone levels and appetite were seen in the 16 people who did not complete the study.
• This was a small study of only 50 people. To draw more accurate conclusions about the effects of dieting in obese people, larger studies are needed. The results of this study may help in designing these.

People who want to lose weight should not be alarmed by this study’s findings or assume that dieting is futile or will damage their hormone balance. Instead, they can see a dietitian or their GP if they are struggling to lose weight or maintain a healthy weight.

Analysis by Bazian

Links To The Headlines

Why dieting makes you FAT: Research shows trying to lose weight alters your brain and hormones so you're doomed to pile it on again. Daily Mail, April 24 2012

Links To Science

Sumithran P, Prendergast LA, Delbridge E et al. Long-Term Persistence of Hormonal Adaptations to Weight Loss. N Engl J Med 2011; 2011.365:1597-1604

How to feel full without pigging out - drink water before a meal

reposted from: New Scientist

How to feel full without pigging out

• 26 August 2010 by Jessica Griggs
• Magazine issue 2775. Subscribe and save
• For similar stories, visit the Food and Drink Topic Guide

TWO ways in which dieters try to make themselves feel full without stuffing themselves with food have been backed up by separate research teams.

One effect of overeating is to disrupt the action of appetite-suppressing hormones, leading people to eat even more. The role of exercise in restoring the hormones' action, and so helping people feel full, has been investigated by a team from the State University of Campinas, Brazil.

The hormones leptin and insulin both act to control appetite by binding to receptors in a brain region called the hypothalamus, initiating the "I'm full" feeling. Overeating generates excess fatty acids that inflame part of the hypothalamus, decreasing the uptake of these hormones.

After exercising lean and obese rats, the team observed their eating habits over the following 12 hours. Obese rats ate about 25 per cent less than they had before their workout but no change was seen in the lean rats' eating habits (PLoS Biology, DOI: 10.1371/journal.pbio.1000465).

The team also found that, after exercising, the obese rats' brains contained dramatically increased levels of anti-inflammatory proteins that are produced during muscle contractions, compared with the lean rats. Co-author José Carvalheira reasons that exercise didn't affect the lean animals' appetite because their hypothalamus was not inflamed.

If exercise doesn't appeal, you could try drinking a few glasses of water before eating a meal. At this week's meeting of the American Chemical Society in Boston, Brenda Davy from Virginia Tech in Blacksburg announced the results of the first clinical trial into this practice. She and her colleagues found that over 12 weeks, adults on a low-calorie diet who drank two glasses of water before meals lost 7 kilograms, while non-water-drinkers lost 5 kilograms.

After the end of the low-calorie diet, water drinkers who continued the practice for 12 months while eating well were better at keeping the weight off. "This is an important finding," says Davy, as keeping off lost weight is a major challenge for people who have been dieting.

Obesity & the Regulation of Body Mass, part 1 (draft), source: Lehninger - Principles of Biochemistry

source: Lehninger Principles of Biochemistry (5th Ed, 2008), Chapter 23.4, pg 930-932

I've recently bought the latest edition of Lehninger Principles of Biochemistry ( 5th Edition, 2008). Chapter 23.4 & 23.5 summarises Obesity & the Regulation of Body Mass. Also see my summary of September 2007 Scientific American article.

To a first approximation, obesity is the result of taking in more calories in the diet than are expended by the body's energy consuming activities. The body can deal with an excess of calories in 3 ways:

1. convert excess fuel to fat and store it in adipose tissue.
2. burn excess fuel by extra exercise.
3. "waste" fuel by diverting it to heat production (thermogenesis) by uncoupled mitochondria.
   

In mamamals a complex set of hormonal and neuronal signals acts to keep fuel intake and energy expenditure in balance, so as to hold the amount of adipose tissue at a suitable level. Dealing effectively with obesity requires understanding these checks and balances under normal conditions, and how these homeostatic conditions can fail.

Adipose tissue has important endocrine functions

FIGURE 23-33 Set-point model for maintaining constant mass. When the mass of adipose tissue increases (dashed outline), released leptin inhibits feeding and fat synthesis and stimulates oxidation of fatty acids. When the mass of adipose tissue decreases (solid outline), a lowered leptin production favors a greater food intake and less fatty acid oxidation.

FIGURE 23-34 Obesity caused by defective leptin production. Both of these mice, which are the same age, have defects in the OB gene. The mouse on the right was injected daily with purified leptin and weighs 35 g. The mouse on the left got no leptin, and consequently ate more food and was less active; it weighs 67 g.

FIGURE 23-35 Hypothalamic regulation of food intake and energy expenditure. (a) Anatomy of the hypothalamus and its interaction with adipose tissue. (b) Details of the interaction between the hypothalamus and an adipocyte, described later in the text.

FIGURE 23-36 Hormones that control eating. In the arcuate nucleus, two sets of neurosecretory cells receive hormonal input and relay neuronal signals to the cells of muscle, adipose tissue, and liver. Leptin and insulin are released from adipose tissue and pancreas, respectively, in proportion to the mass of body fat. The two hormones act on anorexigenic neurosecretory cells to trigger release of α-MSH (melanocortin); this produces neuronal signals to eat less and metabolize more fuel. Leptin and insulin also act on orexigenic neurosecretory cells to inhibit the release of NPY, reducing the "eat" signal sent to the tissues. As described later in the text, the gastric hormone ghrelin stimulates appetite by activating the NPY-expressing cells; PYY3-36, released from the colon, inhibits these neurons and thereby decreases appetite. Each of the two types of neurosecretory cells inhibits hormone production by the other, so any stimulus that activates orexigenic cells inactivates anorexigenic cells, and vice versa. This strengthens the effect of stimulatory inputs.

Leptin, the Appetite Hormone, Rewires the Brain

reposted from: http://www.genomenewsnetwork.org/articles/2004/04/16/leptin.php
search keywords: leptin, appetite, Leptin: wikipedia

Leptin, the Appetite Hormone, Rewires the Brain

By Nancy Touchette

Posted: April 16, 2004

Mice without the leptin gene are morbidly obese (right) compared to normal mice (left). Image courtesy Sebastien Bouret/University of Oregon.

Researchers have discovered that leptin, an appetite-suppressing hormone, works in an unexpected way. The hormone, which has attracted considerable attention as a potential key to weight loss, is produced by fat cells, but it controls hunger by acting on the brain. Now, two new studies in mice show that the hormone works by actually rewiring the neural circuits in the brain.

The research also shows that some of these circuits are set just after birth, presenting the possibility that, at least to a certain extent, the tendency to overeat and gain weight may be hardwired early in life.

Although the new studies were conducted in mice, researchers believe the research may help them understand human obesity because the hormone has the same effect in humans as in mice. Like mice, people who are missing the leptin gene become morbidly obese. But when these rare individuals are given leptin, they lose weight.

Most obese people are not missing the leptin gene and are known to produce leptin. In fact, some have more than enough. Researchers believe that obesity may be caused, in part, by defects in the signaling pathways in the brain that normally respond to leptin.

“We decided early on that the leptin story was going to very complicated,” says Jeffrey Friedman of Rockefeller University in New York City, who led one of the studies. “To move ahead, we have to understand how leptin acts normally and which of its effects are missing in obese individuals.”

Leptin promotes the growth of mouse neurons. Images show growth patterns without leptin (top) and with leptin. Image courtesy Science.

The findings surprised researchers, who thought that leptin worked by activating individual neurons, not by changing the way they connect to each other.

“You can imagine that information flows between neurons much like water through the plumbing system in a house,” says Friedman. “You can regulate this flow by opening and closing valves, or you can add or subtract pipes from the whole system.”

“We thought leptin would act by opening and closing valves. Instead, it appears to add and subtract pipes,” he says.

In the new study, published in Science, Friedman, in collaboration with Tamas L. Horvath at Yale University School of Medicine in New Haven, Connecticut, found that mice without the leptin gene have more connections coming into neurons affected by leptin than do other mice. The result was more circuits that increase appetite—and fat mice.

But when the mice were given leptin, the circuitry was reversed. The mice developed normal neural connections, and normal appetites.

In a second study, also appearing in Science, researchers noted that shortly after birth, both mice and humans experience a surge in leptin levels. This seemed perplexing because leptin normally signals appetite suppression. But newborns need to eat more, not less.

“People didn’t understand this leptin surge,” says Richard Simerly of the Oregon National Primate Research Center in Beaverton, who led the second study. “But we wondered if it was acting as some sort of developmental signal.”

Simerly and his colleagues found that in mice without the leptin gene, the neurons that normally respond to leptin fail to project to other regions of the brain involved in food intake—and the mice become fat.

When Simerly gave the mice leptin immediately after birth, all the neural circuits that control food intake formed normally and the mice maintained normal weight.

However, if the leptin-deficient mice were not given leptin until adulthood, the circuitry was not restored and the mice remained fat.

“We were stunned by this result,” says Simerly. “It told us that leptin acts as a developmental signal that determines the circuits that it acts on later in life.”

Taken together, the two studies suggest that leptin affects two distinct types of neural connections at different times. Early in life, leptin guides output from neurons that affect appetite. Later, leptin signals the input to these same neurons.

Researchers still don’t know what causes the surge in leptin during development or whether it is affected by early feeding habits.

If leptin release in early life is influenced by nutrition, this period could be critical in future weight control.

It’s not yet clear whether the neurons that affect appetite in mice work the same way in humans. But the studies raise the possibility that leptin affects the wiring of a brain circuitry that influences an individual’s weight for life.

“I wouldn’t exactly say that leptin dictates a ‘set weight’” says Simerly. “But in controlling the kinds of neural connections that are made in the brain, leptin may be one of the factors that determines the range of weights a person is likely to have throughout life.”

Pinto, S. et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110-115 (April 2, 2004).

Bouret, S.G. et al. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 110-115 (April 2, 2004).

Elmquist, J.K. and Flier, J.S. The fat-brain axis enters a new dimension. Science 304, (April 2, 2004).

Fine Tuning body weight

reposted from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2582659

I googled: fine tuning body weight, because I'm curious to know how the body fine tunes body weight maintenance. As the article states "Although it is true that weight gain occurs when food intake exceeds energy expenditure, it is important to note that even a 1% mismatch between the two can lead to a substantial weight gain after only a few years." 1% of 2000 calories/day = 20cals/day x 365 days = 7300 cals per year. 3500 cals excess results in one pound increase. So 7300 cals excess = 2 pounds increase per year = 20 pounds over 10 years.

Could there be a fine-tuning role for brain-derived adipokines in the regulation of bodyweight and prevention of obesity? by Russell E. Brown

Abstract: "The body appears to balance energy metabolism via an endogenous lipostatic loop in which adipose stores send hormonal signals (e.g. adipokines such as leptin) to the hypothalamus in order to reduce appetite and increase energy expenditure. However, the brain is also a novel site of expression of many of these adipokine genes. This led to the hypothesis that hypothalamic-derived adipokines might also be involved in bodyweight regulation by exerting some effect on the control of appetite or hypothalamic function." ... Although adipokines secreted by adipose tissue appear to the main regulator of lipostatic loop, this review shows that the fine tuning that is required to maintain a stable bodyweight by this system might be accomplished by hypothalamic-derived adipokines. Perturbations in this central adipokine system could lead to alterations in normal hypothalamic function which leads to unintended weight gain."

Crabsallover Summary: Adipokines derived from the brain (hypothalamus) might control the reduction of appetite and increase energy expenditure, in addition to Adipokines derived from fat (adipose) tissues.