Monash researchers discover how two hormones work together on the brain to stimulate the burning of body fat
By shedding light on the action of two naturally-occurring hormones, Monash University scientists and their collaborators may have discovered a way to assist in the shedding of excess fat.
The researchers have unravelled a molecular mechanism that depends on the combined action of two hormones—leptin, an appetite suppressant generated in fat cells, and insulin, produced in the pancreas in response to rising levels of glucose in the blood. Their paper, published in the journal Cell today, shows that the two hormones act in concert on a group of neurons in the brain to stimulate the burning of body fat via the nervous system.
Their findings may lead to more effective ways of losing weight and preventing obesity by promoting the conversion of white fat to brown fat.
“The combined action of these two hormones makes sense,” says the research group leader Prof Tony Tiganis, a National Health and Medical Research (NHMRC)
Principal Research Fellow in the Department of Biochemistry and Molecular Biology at Monash University and a member of the Monash Obesity & Diabetes Institute (MODI).
“They give the brain a comprehensive picture of the fatness of the body. Because leptin is produced by fat cells, it measures the level of existing fat reserves—the more fat, the more leptin. And because glucose levels rise when we eat, insulin provides a measure of future fat reserves.”
Fat in adult humans is typically stored in adipocytes, specialised cells that comprise white fat. But around the neck and shoulders, there is a second form of fat made of brown adipocytes. Rather than storing fat, these cells can be induced to burn it off.
The Monash researchers have shown that the hormones leptin and insulin interact with proopiomelanocortin (POMC) neurons in the brain’s hypothalamus, causing them to send signals through the nervous system promoting the conversion of white fat into brown fat. This leads to burning off of excess fat.
They found that the process is regulated in these neurons by enzymes known as phosphatases, which inhibit the actions of each of the hormones. Using mice genetically modified to lack these inhibitory enzymes, the researchers were able to show that the browning and burning of fat increases when the levels of these inhibitors are reduced.
“This is a fundamental mechanism that normally serves to maintain body weight,” Tiganis says, “but in diet-induced obesity the process goes awry. And it may involve increasing levels of the two inhibitory enzymes.”
“Eventually, we think we may be able to help people lose weight by pharmacologically targeting these two enzymes,” says Tiganis. “Turning white fat into brown fat is a very exciting new approach to developing weight loss agents. But it is not an easy task, and any potential therapy is a long way off.”
In pursuing his work, Prof Tony Tiganis and the members of his laboratory were assisted by colleagues from Monash and institutions in the US and Canada.
- Professor Tony Tiganis, Monash University, firstname.lastname@example.org; Work phone: +61 3 9902 9332; Mobile: +61 417 396 512
- Lucy Handford, +61 3 9903-4815, +61 427 647 396, email@example.com
- Niall Byrne, +61 417 131 977, firstname.lastname@example.org
Leptin and insulin act on POMC neurons to promote the browning of white fat
The primary task of white adipose tissue (WAT) is the storage of lipids. However, ‘beige’ adipocytes also exist in WAT. Beige adipocytes burn fat and dissipate the energy as heat, but their abundance is diminished in obesity. Stimulating beige adipocyte development, or WAT browning, increases energy expenditure and holds potential for combating metabolic disease and obesity. Here we report that insulin and leptin act together on hypothalamic neurons to promote WAT browning and weight loss. Deletion of the phosphatases PTP1B and TCPTP enhanced insulin and leptin signalling in proopiomelanocortin neurons and prevented diet-induced obesity by increasing WAT browning and energy expenditure. The co-infusion of insulin plus leptin into the CNS or the activation of proopiomelanocortin neurons also increased WAT browning and decreased adiposity. Our findings identify a homeostatic mechanism for coordinating the status of energy stores, as relayed by insulin and leptin, with the central control of WAT browning.
- Prof Tony Tiganis, Department of Biochemistry and Molecular Biology, Monash University
Full author list
Garron Dodd1, Stephanie Descherf1, Kim Loh1, Stephanie E. Simonds2, Florian Wiede1, Eglantine Balland2, Troy L Merry1, Heike Münzberg3, Zhong-Yin Zhang4, Barbara B Kahn5, Benjamin G. Neel6, Kendra K Bence7, Zane B Andrews2, Michael A Cowley2, and Tony Tiganis1
1 Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia
2 Department of Physiology, Monash University, Victoria 3800, Australia
3 Pennington Biomedical Research Center, LSU Systems, Baton Rouge, LA 70808, USA
4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202-5126, USA
5 Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
6 Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital and Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada
7 Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA