Hunger Games: How the brain ‘browns’ fat to aid weight loss

Researchers at Yale School of Medicine have uncovered a molecular process in the brain known to control eating that transforms white fat into brown fat. This process impacts how much energy we burn and how much weight we can lose. The results are published in the Oct. 9 issue of the journal Cell.

Obesity is a rising global epidemic. Excess fatty tissue is a major risk factor for type 2 diabetes, cardiovascular disease, hypertension, neurological disorders, and cancer. People become overweight and obese when energy intake exceeds energy expenditure, and excess calories are stored in the adipose tissues. The adipose organ is made up of both white and brown fat. While white fat primarily stores energy as triglycerides, brown fat dissipates chemical energy as heat. The more brown fat you have, the more weight you can lose.

It has previously been shown that energy-storing white fat has the capacity to transform into energy-burning “brown-like” fat. In this new study, researchers from the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism, demonstrate that neurons controlling hunger and appetite in the brain control the “browning” of white fat.

Lead author Xiaoyong Yang, associate professor of comparative medicine and physiology at Yale School of Medicine, conducted the study with Tamas Horvath, professor and chair of comparative medicine, and professor of neurobiology and Obstetrics/gynecology at Yale School of Medicine, and their co-authors.

The team stimulated this browning process from the brain in mice and found that it protected the animals from becoming obese on a high-fat diet. The team then studied the molecular changes in hunger-promoting neurons in the hypothalamus and found that the attachment of a unique sugar called “O-GlcNAc” to potassium ion channels acts as a switch to control brain activity to burn fat.

“Our studies reveal white fat “browning” as a highly dynamic physiological process that the brain controls,” said Yang. “This work indicates that behavioral modifications promoted by the brain could influence how the amount of food we eat and store in fat is burned.”

Yang said hunger and cold exposure are two life-history variables during the development and evolution of mammals. “We observed that food deprivation dominates over cold exposure in neural control of white fat browning. This regulatory system may be evolutionarily important as it can reduce heat production to maintain energy balance when we are hungry. Modulating this brain-to-fat connection represents a potential novel strategy to combat obesity and associated illnesses.”

Fighting fat with fat: stem cell discovery identifies potential obesity treatment

Ottawa scientists have discovered a trigger that turns muscle stem cells into brown fat, a form of good fat that could play a critical role in the fight against obesity. The findings from Dr. Michael Rudnicki’s lab, based at the Ottawa Hospital Research Institute, were published today in the prestigious journal Cell Metabolism.

"This discovery significantly advances our ability to harness this good fat in the battle against bad fat and all the associated health risks that come with being overweight and obese," says Dr. Rudnicki, a senior scientist and director for the Regenerative Medicine Program and Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute. He is also a Canada Research Chair in Molecular Genetics and professor in the Faculty of Medicine at the University of Ottawa.

Globally, obesity is the fifth leading risk for death, with an estimated 2.8 million people dying every year from the effects of being overweight or obese, according to the World Health Organization. The Public Health Agency of Canada estimates that 25% of Canadian adults are obese.

Globally, obesity is the fifth leading risk for death, with an estimated 2.8 million people dying every year from the effects of being overweight or obese, according to the World Health Organization. The Public Health Agency of Canada estimates that 25% of Canadian adults are obese.

In 2007, Dr. Rudnicki led a team that was the first to prove the existence of adult skeletal muscle stem cells. In the paper published today, Dr. Rudnicki now shows (again for the first time) that these adult muscle stem cells not only have the ability to produce muscle fibres, but also to become brown fat. Brown fat is an energy-burning tissue that is important to the body’s ability to keep warm and regulate temperature. In addition, more brown fat is associated with less obesity.

Perhaps more importantly, the paper identifies how adult muscle stem cells become brown fat. The key is a small gene regulator called microRNA-133, or miR-133. When miR-133 is present, the stem cells turn into muscle fibre; when reduced, the stem cells become brown fat.

Dr. Rudnicki’s lab showed that adult mice injected with an agent to reduce miR-133, called an antisense oligonucleotide or ASO, produced more brown fat, were protected from obesity and had an improved ability to process glucose. In addition, the local injection into the hind leg muscle led to increased energy production throughout the body—an effect observed after four months.

Using an ASO to treat disease by reducing the levels of specific microRNAs is a method that is already in human clinical trials. However, a potential treatment using miR-133 to combat obesity is still years away.

"While we are very excited by this breakthrough, we acknowledge that it’s a first step," says Dr. Rudnicki, who is also scientific director of the Stem Cell Network. "There are still many questions to be answered, such as: Will it help adults who are already obese to lose weight? How should it be administered? How long do the effects last? Are there adverse effects we have not observed yet?"

The brain circuit that makes it hard for obese people to lose weight

Imagine you are driving a car, and the harder you press on the accelerator, the harder an invisible foot presses on the brake. That’s what happens when obese people diet – the less food they eat, the less energy they burn, and the less weight they lose.

While this phenomenon is known, scientists at Sydney’s Garvan Institute of Medical Research and the University of NSW have pinpointed the exact brain circuitry behind it and have published their findings in the prestigious international journal Cell Metabolism, now online.

Dr Shu Lin, Dr Yanchuan Shi and Professor Herbert Herzog and his team have been studying the complex processes behind energy balance using various mouse models. They have shown that the neurotransmitter Neuropeptide Y (NPY), known for stimulating appetite, also plays a major role in controlling whether the body burns or conserves energy.

The researchers found that NPY produced in a particular region of the brain – the arcuate nucleus (Arc) of the hypothalamus – inhibits the activation of ‘brown fat’, one of the primary tissues where the body generates heat.

“This study is the first to identify the neurotransmitters and neural pathways that carry signals generated by NPY in the brain to brown fat cells in the body. It is also the first to show a direct connection between Arc NPY, the sympathetic nervous system and the control of energy expenditure.” said Professor Herzog.

“We know that NPY also influences other aspects of the sympathetic nervous system – such as heart rate and gut function – but its control of heat generation through brown fat seems to be the most critical factor in the control of energy expenditure.”

“When you don’t eat, or dramatically curtail your calorie intake, levels of NPY rise sharply. High levels of NPY signal to the body that it is in ‘starvation mode’ and should try to replenish and conserve as much energy as possible. As a result, the body reduces processes that are not absolutely necessary for survival.”

“Evolution has provided us with these mechanisms to help us survive famine, and they are strictly controlled. When people had to survive by finding food or hunting game, they could not afford to run out of energy and die of exhaustion, so their bodies evolved to cope.”

“Until the twentieth century, there were no fast food chains and people did not have ready access to high fat, high sugar, foods. So in evolutionary terms, it was unlikely that people were going to get very fat and mechanisms were only put in place to prevent you losing weight.”

“Obesity is a modern epidemic, and the challenge will be to find ways of tricking the body into losing weight – and that will mean somehow circumventing or manipulating this NPY circuit, probably with drugs.”