Blocking a muscle growth-limiting hormone protects against obesity and atherosclerosis

Knockout of myostatin, a growth factor that limits muscle growth, can decrease body fat and promote resistance against developing atherosclerosis, or “hardening” of the arteries, according to a new study conducted in mice. The results will be presented Thursday at The Endocrine Society’s 91st Annual Meeting in Washington, D.C.

“Obesity increases the risk of atherosclerosis, which accounts for 75% of all cardiovascular events, such as heart attacks and strokes,” said study co-author Shalender Bhasin, MD, professor of medicine at Boston University School of Medicine and chief of the Section of Endocrinology, Diabetes, and Nutrition at Boston Medical Center. “Current strategies aimed at preventing heart disease consist primarily of lowering cholesterol levels, but patients reaching the desired cholesterol levels are still at risk for atherosclerosis if they have other risk factors, such as obesity.”

Humans and animals with a mutation in the myostatin gene are extremely muscular and have little fat, past research shows. Also, when the gene encoding myostatin is knocked out in mice, their muscle mass increases.

Bhasin and his co-workers wanted to find out if inhibiting myostatin in mice could resist the development of diet-induced obesity and of atherosclerosis, the buildup of lipid deposits called plaque that can narrow and clog coronary arteries.

The researchers took mice that were genetically altered to develop atherosclerosis and then cross-bred them with myostatin knockout mice. Ten generations later, they had mice who were genetically predisposed to both atherosclerosis and inactivation of myostatin. For controls, they studied mice with a genetic predisposition for atherosclerosis but with intact myostatin gene. All mice received a high-fat diet for 12 weeks, to spur the development of atherosclerosis.

Compared with controls, the mice with deleted myostatin gene had much less body fat and 30 percent lower fasting blood sugar and 80% lower fasting insulin levels, showing a reduction in obesity and a strong resistance to developing diabetes, the authors reported. They also had 50 percent lower low-density-lipoprotein (“bad”) cholesterol and 30 to 60 percent lower levels of total cholesterol and triglycerides (fats in the blood), respectively. These results indicate protection against the development of atherosclerosis, according to Bhasin.

More research is needed to demonstrate the safety and effectiveness of myostatin inhibitors in humans, Bhasin said. However, he said that that this therapeutic strategy already is possible. Experimental drugs called myostatin blockers or inhibitors are being studied as potential treatments of muscle wasting disorders and limb injuries.

Some currently available nutritional supplements are touted as myostatin inhibitors, but Bhasin said he doubts they are effective.

BOSTON (May 18, 2009) Curcumin, the major polyphenol found in turmeric, appears to reduce weight gain in mice and suppress the growth of fat tissue in mice and cell models. Researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University (USDA HNRCA) studied mice fed high fat diets supplemented with curcumin and cell cultures incubated with curcumin.

“Weight gain is the result of the growth and expansion of fat tissue, which cannot happen unless new blood vessels form, a process known as angiogenesis.” said senior author Mohsen Meydani, DVM, PhD, director of the Vascular Biology Laboratory at the USDA HNRCA. “Based on our data, curcumin appears to suppress angiogenic activity in the fat tissue of mice fed high fat diets.”

Meydani continued, “It is important to note, we don’t know whether these results can be replicated in humans because, to our knowledge, no studies have been done.”

Turmeric is known for providing flavor to curry. One of its components is curcumin, a type of phytochemical known as a polyphenol. Research findings suggest that phytochemicals, which are the chemicals found in plants, appear to help prevent disease. As the bioactive component of turmeric, curcumin is readily absorbed for use by the body.

Meydani and colleagues studied mice fed high fat diets for 12 weeks. The high fat diet of one group was supplemented with 500 mg of curcumin/ kg diet; the other group consumed no curcumin. Both groups ate the same amount of food, indicating curcumin did not affect appetite, but mice fed the curcumin supplemented diet did not gain as much weight as mice that were not fed curcumin.

“Curcumin appeared to be responsible for total lower body fat in the group that received supplementation,” said Meydani, who is also a professor at the Friedman School of Nutrition Science and Policy at Tufts. “In those mice, we observed a suppression of microvessel density in fat tissue, a sign of less blood vessel growth and thus less expansion of fat. We also found lower blood cholesterol levels and fat in the liver of those mice. In general, angiogenesis and an accumulation of lipids in fat cells contribute to fat tissue growth.”

Writing in the May 2009 issue of the Journal of Nutrition, the authors note similar results in cell cultures. Additionally, curcumin appeared to interfere with expression of two genes, which contributed to angiogenesis progression in both cell and rodent models.

“Again, based on this data, we have no way of telling whether curcumin could prevent fat tissue growth in humans.” Meydani said. “The mechanism or mechanisms by which curcumin appears to affect fat tissue must be investigated in a randomized, clinical trial involving humans.”

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This study was funded by a grant from the United States Department of Agriculture. Asma Ejaz, a graduate student who worked on this project received a scholarship grant from the Higher Education Commission of Pakistan.

Ejaz A, Wu, D, Kwan P, and Meydani M. Journal of Nutrition. May 2009; 139 (5): 1042-1048. “Curcumin Inhibits Adipogenesis in 3T3-L1 Adipocytes and Angiogenesis and Obesity in C57/BL Mice. 919-925.”

Basically, the two ratty cohorts were fed more than sufficient, except one group was supplemented with arginine and the other alanine (another amino acid) as a control. The rats fed arginine put on far less weight than the controls.

They also concluded that supplementation with arginine shifts nutrient partitioning to promote skeletal-muscle gain.

It’s not really clear how the amounts given to the rats translate to a human-sized dose, nor is it clear as to the mechanism whereby arginine does this, but to my reckoning it might have something to do with this: “Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion“.

Regardless, given that I hate hate hate fat, I might just buy a tub next time I’m at the shop and see if it does anything besides:

• Acting as a precursor for the synthesis of nitric oxide (NO)
• Improving immune function
• Reducing healing time of injuries (particularly bone)
• Quickening repair time of damaged tissue
• Reducing risk of heart disease
• Helping to improve insulin sensitivity
• Helping to decrease blood pressure
• Alleviating male infertility, improving sperm production and motility
• Increasing circulation throughout the body, including the sex organs

Even if only the last one comes true, I think it’ll be worth the price!!

Here’s the abstract:

Dietary L-arginine supplementation reduces white fat gain and enhances skeletal muscle and brown fat masses in diet-induced obese rats.

J Nutr. 2009 Feb;139(2):230-7. Epub 2008 Dec 23. PMID: 19106310

Previous studies showed that dietary L-arginine supplementation decreased white fat mass in genetically obese rats. This study tested the effectiveness of L-arginine in diet-induced obesity. Male Sprague-Dawley rats were fed for 15 wk a high-fat (HF) (40% energy) or low-fat (LF) (10% energy) diet beginning at 4 wk of age, resulting in 18% higher body weight gains and 74% higher weights of major white fat pads (retroperitoneal, epididymal, subcutaneous, and mesenteric adipose tissues) in HF than in LF fed rats. Starting at 19 wk of age, rats in each dietary group were supplemented for 12 wk with 1.51% L-arginine-HCl or 2.55% L-alanine (isonitrogenous control) (n = 8 per treatment) in drinking water and arginine groups were individually pair-fed to alanine controls. Despite similar energy intake, absolute weights of white fat pads increased by 98% in control rats over a 12-wk period but only by 35% in arginine-supplemented rats. The arginine treatment reduced the relative weights of white fat pads by 30% and enhanced those of soleus muscle by 13%, extensor digitorum longus muscle by 11%, and brown fat by 34% compared with control rats. Serum concentrations of insulin, adiponectin, growth hormone, corticosterone, triiodothyronine, and thyroxine did not differ between control and arginine-supplemented rats. However, arginine treatment resulted in lower serum concentrations of leptin, glucose, triglycerides, urea, glutamine, and branched-chain amino acids, higher serum concentrations of nitric-oxide metabolites, and improvement in glucose tolerance. Thus, dietary arginine supplementation shifts nutrient partitioning to promote muscle over fat gain and may provide a useful treatment for improving the metabolic profile and reducing body white fat in diet-induced obese rats.

Most of us experience weight gain over winter, and I had always assumed that it was due to the changes in lifestyle that the winter months necessitate. Physical activity is curtailed because of bad weather; gymming is often eschewed in favor of curling up at home; and heavy, energy-dense food somehow becomes incredibly appetizing. In the northern hemisphere, winter also brings holiday celebrations and wanton feasting.

Certainly, these factors contribute to the winter bulge, but the new idea presented by Dr. Y.J. Foss is that winter weight-gain is an actual physiological, adaptive response by the body to the hardships of winter, and that it’s controlled by the body’s vitamin D status.

Although most people tend to think that the cause of obesity has solely to do with the consumption of excess food and a lack of exercise, there are still factors that defy explanation.

For example, if we assume that the cause of obesity is a mismatch between genes and environment – i.e., some people have a ‘thrifty’ genotype, one that prefers to conserve energy, and they live in the modern western world, where there is an overabundance of food and little need for physical activity, it remains unknown why there is such a difference between different individuals in the same environment. However, if we invoke genetic differences between people as the explanation for individual differences, there is no explanation for why the initiation of weight gain occurs at different points in the course of a person’s life, nor is there an explanation for large-scale trends towards weight gain depending on geographical location, industrialization, and other societal differences.

Also, it remains that most interventions that focus on altering the lifestyle of the overweight individual fail in the long term, which suggests the existence of an as-yet-unexplained causative factor for weight gain.

Therefore, the hypothesis that vitamin D deficiency might be the missing link has been presented.

The body has a seasonal cycle that tends to favor energy storage during the cold, winter months. This ‘winter response’ is thought to be controlled by the levels of circulating vitamin D, which is synthesized by the skin in response to UV light.

So think about it:

• Even fat people usually don’t tend to constantly increase in weight – even though they experienced weight gain, there is some kind of brain-controlled mechanism that keeps their weight stable, even if excessive
• Animals also have a tendency to be larger in cooler climates, indicating weight-gain is a controlled, adaptive response to the environment
• What we consider to be ‘metabolic syndrome’ is actually very similar, if not identical, to the “winter metabolism”

So, it now remains to be tested whether obese individuals have lower plasma calcidiol levels (the form of vitamin D that fluctuates most according to exposure to sunlight). It’s a very exciting theory, because vitamin D deficiency has the potential to explain both large scale trends and individual variation with regard to obesity. It can be inferred that on a population-wide scale, vitamin D status has fallen in line with the increase in obesity – both obesity and low vitamin D status are both artifacts of the urban-industrial lifestyle. Whether the two are linked will be investigated in future study.

One wonders if our friend in the picture above would do well to make a habit of what he’s currently doing.

Reference: Foss YJ, Vitamin D de?ciency is the cause of common obesity, Med Hypotheses (2008), doi:10.1016/j.mehy.2008.10.005
Photo credit: Kyle May on Flickr

The team, headed by Professor Gerald I. Shulman, investigated substances known as N-acylphosphatidylethanolamines, or NAPEs, which are synthesized and secreted into the blood by the small intestine after fatty foods are eaten. When rats and mice were regularly injected with NAPEs, they experienced suppressed appetites and reduced their food intake.

It is believed NAPEs reduce the activity of hunger neurons in the brain and stimulate satiety neurons. I know, this is a rather obtuse description, but what it means is that NAPEs act on the brain itself to suppress appetite as opposed to some other physiological effect, like causing the stomach to contract or whatnot.

While NAPEs have not yet been tested in humans, that’s the very next thing on the agenda for the researchers at Yale, and who knows – a NAPE-based anti-fat pill could be prescribed to you in the not too distant future.

The findings will be published in the 26 November 2008 issue of Cell and were brought to my attention through a Eurekalert! press release.

The prestigious and excellent-for-a-laugh International Journal of Obesity reported today that fatness and stupidity are actually linked at a physiological level. Cortisol, a hormone released in moments of stress and as a result of obesity, causes a decline in cognitive performance.

In this experiment, they decided to induce stress by making their test subjects go skydiving! While nervously cruising to the drop zone, the scientists took saliva samples and made the participants perform IQ tests that measured a broad range of cognitive functions.

The fat group experienced significantly greater cortisol spikes than the normal-weight group. Not only that, but they performed significantly worse on the cognitive tests (compared to baseline) than their normal-weight counterparts.

So what does this mean?

1. Don’t take fat people skydiving because they’ll freak out, lose their minds, and just do something irrational and unnpredictable
2. Staying relaxed is key to operating at 100% cognitive efficiency

I would once again like to point out that while I enjoy ridiculing fat people, I have nothing fundamentally against them and hope that they can one day be brought to a state of ruddy, muscular, and extremely sexy health with something as easy as popping a single pill. However, I do want people to think twice before they let themselves slide down that slippery slope of cakes, chips, and complete and chronic inactivity.

Photo credit: Bedtime Champ, Flickr