Health  

Scientists have discovered the mechanism underlying the genomic region most strongly associated with obesity. The research, that uses CRISPR methods, has uncovered a genetic pathway that controls whether our bodies burn or store fat. Manipulating that genetic circuit could offer a new approach for obesity treatments.

Obesity is one of the biggest public health challenges today. Wih more than 500 million people affected worldwide, obesity costs at least $200 billion each year in the United States alone, and contributes to potentially fatal disorders such as cardiovascular disease, diabetes, and cancer.

Now a new approach to prevent and even cure obesity may soon be available, after a study led by researchers at MIT and Harvard Medical School and published in the New England Journal of Medicine.

By analyzing the cellular circuitry underlying the strongest genetic association with obesity, the researchers have unveiled a new pathway that controls human metabolism by prompting our adipocytes, or fat cells, to store fat or burn it away.

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“Obesity has traditionally been seen as the result of an imbalance between the amount of food we eat and how much we exercise, but this view ignores the contribution of genetics to each individual’s metabolism,” says senior author Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and of the Broad Institute.

"Our results indicate that the obesity-associated region acts primarily in adipocyte progenitor cells in a brain-independent way."

The strongest association with obesity resides in a gene region known as “FTO,” which has been the focus of intense scrutiny since its discovery in 2007. However, previous studies have failed to find a mechanism to explain how genetic differences in the region lead to obesity.

“Many studies attempted to link the FTO region with brain circuits that control appetite or propensity to exercise,” says first author Melina Claussnitzer, a visiting professor at CSAIL and instructor in medicine at Beth Israel Deaconess Medical Center and Harvard Medical School. “Our results indicate that the obesity-associated region acts primarily in adipocyte progenitor cells in a brain-independent way.”

To recognize the cell types where the obesity-associated region may act, the researchers used annotations of genomic control switches across more than 100 tissues and cell types. They found evidence of a major control switchboard in human adipocyte progenitor cells, suggesting that genetic differences may affect the functioning of human fat stores.

The researchers that the risk version activated a major control region in adipocyte progenitor cells, which turned on two distant genes, IRX3 and IRX5.

Follow-up experiments showed that IRX3 and IRX5 act as master controllers of a process known as thermogenesis, whereby adipocytes dissipate energy as heat, instead of storing it as fat.

Thermogenesis can be triggered by exercise, diet, or exposure to cold, and occurs both in mitochondria-rich brown adipocytes that are developmentally related to muscle, and in beige adipocytes that are instead related to energy-storing white adipocytes.

“Early studies of thermogenesis focused primarily on brown fat, which plays a major role in mice, but is virtually nonexistent in human adults,” Claussnitzer says. “This new pathway controls thermogenesis in the more abundant white fat stores instead, and its genetic association with obesity indicates it affects global energy balance in humans.”

The researchers predicted that a genetic difference of only one nucleotide is responsible for the obesity association. In risk individuals, a thymine (T) is replaced by a cytosine (C) nucleobase, which disrupts repression of the control region and turns on IRX3 and IRX5. This then turns off thermogenesis, leading to lipid accumulation and ultimately obesity.

By editing a single nucleotide position using the CRISPR/Cas9 system — a technology that allows researchers to make precise changes to a DNA sequence — the researchers could switch between lean and obese signatures in human pre-adipocytes.

Switching the C to a T in risk individuals turned off IRX3 and IRX5, restored thermogenesis to non-risk levels, and switched off lipid storage genes.

“Knowing the causal variant underlying the obesity association may allow somatic genome editing as a therapeutic avenue for individuals carrying the risk allele,” Kellis says. “But more importantly, the uncovered cellular circuits may allow us to dial a metabolic master switch for both risk and non-risk individuals, as a means to counter environmental, lifestyle, or genetic contributors to obesity.”

"Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects," conclude the researchers in their paper.

The researchers work could lead to therapies that manipulate this new pathway to reverse the signatures of obesity in both human cells and mice.

“By manipulating this new pathway, we could switch between energy storage and energy dissipation programs at both the cellular and the organismal level, providing new hope for a cure against obesity,” Kellis says.

SOURCE  MIT News

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 Weight Loss  

A drug approved to treat overactive bladder may boost brown fat's metabolic capabilities, making it a promising candidate for weight loss. Brown fat burns energy to generate heat, which can help maintain body weight and prevent obesity.

Researchers have discovered that a drug FDA-approved to treat overactive bladder may boost brown fat's metabolic powers, making it a promising candidate weight loss treatment. Unlike energy-storing white fat, brown fat burns energy to generate heat, which can help maintain body weight and prevent obesity in rodents.

Brown fat makes up about 5% of the fat in newborn infants, and is thought to be a critical mechanism for thermal regulation in babys.  In adults it is found in the upper chest and neck in small amounts typically.  Brown fat has recently been found to be part of the skeletal muscle system, and is stimulated by cold exposure.

"Brown adipose tissue, or brown fat, produces β3-adrenergic receptor at levels higher than nearly every other organ in the body. We showed that a one-time dose of the drug mirabegron stimulates human brown adipose tissue so that it consumes glucose and burns calories."

Previous studies have found that brown fat can be coaxed into action by activating the β3-adrenergic receptor, which is expressed on the surfaces of brown and white fat cells, as well as on cells of the urinary bladder and other tissues.  Following up this research, the investigators wondered whether mirabegron, a drug that targets the β3-adrenergic receptor and was recently approved to treat overactive bladder, might help keep people's weight in check.

In all 12 men enrolled in the study, 200 milligrams of mirabegron led to higher brown fat metabolic activity, and at its peak level in the blood it increased the men's resting metabolic rate by 203 calories per day. While the dose was higher than the 50 milligram dose approved for overactive bladder, the treatment was well tolerated. All of the study participants were young, healthy individuals who had not previously taken mirabegron.

The study was published recently in the journal Cell Metabolism.

"Brown adipose tissue, or brown fat, produces β3-adrenergic receptor at levels higher than nearly every other organ in the body. We showed that a one-time dose of the drug mirabegron stimulates human brown adipose tissue so that it consumes glucose and burns calories," said lead author Dr. Aaron Cypess, who conducted the work at Joslin Diabetes Center and Beth Israel Deaconess Medical Center, affiliates of Harvard Medical School, and is now at the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health.

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The findings suggest that drugs that activate the β3-adrenergic receptor may be a promising treatment for obesity. "Prior to our work, the only known way to activate human brown adipose tissue was through cold exposure. While inexpensive, this approach is generally not well tolerated over the long term, and there is significant variability in people's responses," said Dr. Cypess. "In addition, once the cold exposure is removed, the effect usually turns off rather quickly."

Cold showers are now touted as a way to stimulate brown fat, but further research may find ways to prolong the effects on brown fat.

Dr. Cypess noted that in addition to attempts to activate brown fat, strategies that produce more of it might also help treat people with metabolic conditions. Other research groups are also generating promising results through the use of drugs to convert white fat cells into brown fat and through discoveries of the pathways and hormones that control brown fat metabolism.


SOURCE  Cell Press via EurekAlert

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