Scientists have identified a powerful pathway originating from the brain that causes rapid reductions in overall body fat, including stubborn fat deposits that normally resist diet and exercise. This process works independently of the nervous system signals that normally cause fat loss, and instead relies on specific conditions of low blood sugar and low insulin. The research results were published in a magazine natural metabolism.
Survival depends on the body’s ability to store and mobilize calories when it is most needed. Most fat cells release energy in response to typical signals such as fasting and physical activity. However, humans and other mammals have a specialized population of fat cells known as stable adipocytes, which do not change much during normal caloric restriction or exercise.
These stable fat cells make up about 70% of the fat found deep within the human bone marrow. Scientists wanted to understand why these particular fat cells resist typical weight loss cues and how the body ultimately breaks them down under extreme conditions. In severe starvation or debilitating illness, the body eventually uses up these stable fat reserves. Until now, the exact biological mechanisms controlling this final stage of fat loss were unknown because scientists lacked reliable animal models.
“Certain fat cells in the body are stable and resistant to diet and exercise. We wanted to understand why and how to deplete them,” said study author Erica L. Scherer, associate professor of medicine at the University of Washington and executive director of the Washington University Center for Regenerative Medicine.
To investigate this phenomenon, researchers developed a new procedure that rapidly caused a reduction in overall body fat in adult male mice aged 12 to 17 weeks. They continuously delivered a hormone called leptin, which normally regulates energy balance, directly into the mice’s brains.
Delivery was achieved using a microscopic pump implanted under the skin and connected to the brain. The researchers administered either 10 nanograms or 100 nanograms of leptin per hour for nine days. They tightly controlled the food intake of these mice, matching them exactly to a control group of mice fed a harmless saline solution.
Over nine days, mice given the highest dose of brain-directed leptin lost an average of 19.3 percent of their body weight. This occurred despite consuming exactly the same amount of food as control mice. Scientists have observed a specific gradual pattern of fat loss.
Fat that regularly accumulated under the skin and around organs disappeared within the first few days of the experiment. Stable fat hidden deep within the bone marrow was much more resistant to treatment. This deep skeletal fat was completely reduced only by day 9 in mice receiving the highest doses of leptin.
Researchers initially suspected that local nerves and stress hormones called catecholamines, such as adrenaline, were causing this extreme fat loss. To test this, they surgically severed the sciatic nerve in one leg of several mice, neutralizing the local nervous system. In another experiment, they used special chemicals to destroy sympathetic nerves throughout the body in another group of mice.
The researchers also tested genetically engineered mice aged 9 to 12 months that were unable to produce certain stress hormones at all. Surprisingly, removing nerves and stress hormones did not prevent extreme fat loss. This provides evidence that the brain communicates with these stable fat cells in an entirely different way via the bloodstream.
Further testing revealed that continuous leptin delivery causes mice to simultaneously experience hypoglycemia and low insulin levels. This particular physical condition is clinically known as hypoinsulinemic hypoglycemia.
To see if this physical condition was responsible for fat loss, the scientists implanted insulin pellets subcutaneously in a new group of mice treated with leptin. The artificial implant returned circulating insulin to normal levels in the mice. Restoring insulin selectively protected stable bone marrow fat from being broken down, but normal body fat still disappeared. This suggests that a precise combination of low blood sugar and low insulin is required to release these stubborn fat deposits.
“We were very surprised that the activation of stable fat cell loss by the brain occurred through signals in the blood and did not involve the peripheral nervous system,” Scherer told PsyPost. “This is different from the standard nervous system that traditionally regulates fat storage.”
The scientists then used advanced genetic sequencing techniques to examine the genetic makeup of these stable fat cells. They found that under normal conditions, stable fat cells produce high levels of a specific protein that acts as an internal brake. One big brake is a protein called G0S2, which blocks the mechanisms inside cells that break down stored fat.
When the mice experienced hypoglycemia and low insulin, production of this G0S2 protein was significantly reduced. Once this internal brake is removed, an enzyme called adipose triglyceride lipase is finally able to break down the accumulated fat. This biological process is known as lipolysis and is how the body turns stored fat into usable energy.
The researchers also observed this exact process in another group of mice that experienced severe tumor-induced weight loss. They injected colon cancer cells into 12-week-old adult mice to induce a severe and debilitating disease known as cachexia. On the final days of cancer progression, these mice experienced exactly the same declines in blood sugar, insulin, and G0S2 protein. This suggests that this newly discovered biological pathway represents a universal response to extreme physical stress.
“In mice, stable activation of fat catabolic pathways reduces all body fat within nine days without reducing food intake,” Scherer said. “In the future, titration of efficacy could inform fat loss treatments and support healthy fat stores in patients with cachexia and debilitating diseases.”
These findings provide insight into how the body burns fat, but researchers caution against considering this as a potential weight loss strategy. These stable fat deposits tend to provide the necessary mechanical and physical support to important body structures.
Depleting these specialized fat cells is considered dangerous. In human patients, depletion of bone marrow fat causes severe consequences such as bone fractures. One potential misconception of this study is that a standard diet can cause this extreme fat loss, but the researchers note that a typical diet does not cause the severe biological conditions necessary to activate this pathway.
This study was primarily conducted in mice, so the exact timeline and biochemical thresholds may be slightly different in humans. Furthermore, the precise blood-based signals that interact with adipocytes after the internal brake is released remain unidentified. Scientists believe that multiple circulating factors may work together to complete the final lipolysis process.
Scientists hope that understanding this newly discovered biological pathway will ultimately inform targeted medical interventions. By blocking this particular fat loss pathway, doctors may be able to support healthy fat storage in critically ill patients. This may ultimately improve survival rates and overall quality of life for these vulnerable patients.
“Wasting is the debilitating result of diseases such as cancer, chronic infections, and end-stage organ failure,” says Dr. Scherer. “Muscle and fat atrophy can reduce a patient’s ability to tolerate necessary chemotherapy and treatments and can significantly contribute to loss of life. We hope to use this research to discover new points of intervention to prevent pathological fat loss and improve survival rates.”
( PubMed ) Xiao Zhang, Sreejith S. Panicker, Jordan M. Bollinger, Anurag Majumdar, Rami Kheireddine, Lila F. Dabill, Clara Kim, Brian Kleiboeker, Fengrui Zhang, Yongbin Chen, and Kristann L. Magee. Learman, Adam Kepecs, Gretchen A. Meyer, Jun Liu, Steven A. Thomas, Irfan J. Lodhi, Ormond A. MacDougald, and Erica L. Scheller.
