Discovery explains how cellular pathways converge to regulate food intake and body weight
July 3, 2012 in Medical research
In the complex chain of molecular events that underlie eating behaviors and body weight, the AMP-activated protein kinase (AMPK) enzyme has proven to be a critical link.
Now, researchers at Beth Israel Deaconess Medical Center (BIDMC) have identified the mechanism responsible for inhibition of AMPK activity in the hypothalamus, a discovery that not only provides a deeper understanding of energy balance but also reveals a critical integration point where multiple signaling pathways, including PI3K-AKT and mTOR converge.
Described in the July 3 issue of Cell Metabolism, the findings could yield new opportunities for the development of treatments for both metabolic diseases and cancer.
"AMPK is an evolutionarily conserved 'fuel gauge,'" says senior author Barbara Kahn, MD, a scientist in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and the George Richards Minot Professor of Medicine at Harvard Medical School. Activated when cellular energy supplies are low, AMPK also functions at the whole body level to regulate metabolism and energy balance.
The Kahn laboratory was the first to describe AMPK's critical role in mediating the actions of leptin, the hormone produced by fat cells that serves as a master regulator of neuroendocrine, metabolic, vascular, sympathetic and immune function. In 2002, Kahn demonstrated that AMPK is activated by leptin in skeletal muscle, thereby enabling the hormone to metabolize fatty acids. Subsequently, in 2004, her laboratory discovered that an opposing scenario takes place in the brain's hypothalamus, where AMPK is inhibited by leptin.
"Having determined that leptin's effects on food intake and body weight depend on the inhibition of AMPK in the hypothalamus, we wanted to determine the signaling events that were responsible for this effect," she explains.
The PI3K-AKT, mTOR-p70S6 kinase and AMPK pathways play distinct and critical roles in metabolic regulation, and each pathway is necessary for leptin's anorexigenic effects in the hypothalamus, which inhibit food intake. Through a series of experiments led by first author Yossi Dagon, PhD, a postdoctoral fellow in the Kahn lab, the scientific team showed that these pathways converge in an integrated phosphorylation cascade to mediate leptin action on the hypothalamus.
"Our findings identify a novel serine phosphorylation site on the AMPK alpha 2 catalytic subunit that mediates leptin's inhibitory effects and is critical for leptin action on food intake and body weight, and further show that ribosomal p70S6 kinase is an inhibitory AMPK kinase," says Kahn. 'These discoveries unify what were thought to be multiple parallel pathways affecting leptin action including PI3 kinase and AKT into a coordinated phosphorylation cascade."
Adds study coauthor Lewis Cantley, PhD, Director of BIDMC's Cancer Center and a leader in the field of cancer metabolism, "Since PI3K, AKT, mTOR and p70S6K have all been shown to be important in cancer biology, this integration of these pathways may be important for cancer and other human diseases and could lead to improved therapeutic approaches."
Obesity has reached epidemic proportions worldwide and increases the risk for developing diabetes, cardiovascular disease and early mortality. "Maintaining normal body weight requires tight control of energy homeostasis, which necessitates a constant flow of metabolic input to the hypothalamus in the form of nutrients and hormones," says Kahn. "Our new results have broad biologic implications, since mTOR-p70S6 kinase and AMPK have multiple, fundamental and generally opposing cellular effects that regulate metabolism, cell growth and development."
Journal reference:
Cell Metabolism
Provided by
Beth Israel Deaconess Medical Center
-
AMPK amplifies Huntington's disease
Jul 18, 2011 |
not rated yet |
0
-
Oncogene inhibits tumor suppressor to promote cancer: Study links B-RAF and LKB1
Jan 29, 2009 |
not rated yet |
0
-
Voluntary exercise by animals prevents weight gain, despite high-fat diet
May 18, 2011 |
not rated yet |
0
-
Scientists study excess fat in chickens
Jan 30, 2008 |
not rated yet |
0
-
Key enzyme plays roles as both friend and foe to cancer
Jun 14, 2012 |
not rated yet |
0
-
Motion perception revisited: High Phi effect challenges established motion perception assumptions
Apr 23, 2013 |
3 / 5 (2) |
2
-
Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update)
Apr 02, 2013 |
4.5 / 5 (11) |
5
-
The visual system as economist: Neural resource allocation in visual adaptation
Mar 30, 2013 |
5 / 5 (2) |
9
-
Separate lives: Neuronal and organismal lifespans decoupled
Mar 27, 2013 |
4.9 / 5 (8) |
0
-
Sizing things up: The evolutionary neurobiology of scale invariance
Feb 28, 2013 |
4.8 / 5 (10) |
14
-
Why is zone 1 in liver more prone to ischemic injury?
4 hours ago
-
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013
-
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013
-
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013
-
If you became brain-dead, would you want them to pull the plug?
May 17, 2013
-
MRI bill question
May 15, 2013
- More from Physics Forums - Medical Sciences
More news stories
Researchers develop sperm-sorting design that may aid couples undergoing in vitro fertilization
(Medical Xpress)—According to the World Health Organization, approximately 70 million couples experience infertility worldwide. Current data suggests that nearly one third of infertility disorders are due ...
Medical research
3 minutes ago |
not rated yet |
0
Baby's life saved with groundbreaking 3-D printed device that restored his breathing
Every day, their baby stopped breathing, his collapsed bronchus blocking the crucial flow of air to his lungs. April and Bryan Gionfriddo watched helplessly, just praying that somehow the dire predictions ...
Medical research
15 hours ago |
5 / 5 (2) |
0
Research shows how immune system peacefully co-exists with 'good' bacteria
The human gut is loaded with commensal bacteria – "good" microbes that, among other functions, help the body digest food. The gastrointestinal tract contains literally trillions of such cells, and yet the ...
Medical research
19 hours ago |
5 / 5 (3) |
0
|
Slowing the aging process—only with antibiotics
Swiss scientists reveal the mechanism responsible for aging hidden deep within mitochondria—and dramatically slow it down in worms by administering antibiotics to the young.
Medical research
19 hours ago |
4.9 / 5 (10) |
1
|
How healthy are you for your age?
On May 22, JoVE will publish details of a technique to measure the health of human genetic material in relation to a patient's age. The method is demonstrated by the laboratory of Dr. Gil Atzmon at New York's Albert Einste ...
Medical research
22 hours ago |
not rated yet |
0
Researchers find possible 'master switch' in deadly brain cancer
(Medical Xpress)—Researchers at the University of Virginia School of Medicine have identified a promising target for treating glioblastoma, one that appears to avoid many of the obstacles that typically frustrate efforts ...
Depression linked to telomere enzyme, aging, chronic disease
(Medical Xpress)—The first symptoms of major depression may be behavioral, but the common mental illness is based in biology—and not limited to the brain.
Vaccine blackjack: IL-21 critical to fight against viral infections
(Medical Xpress)—Scientists at Emory Vaccine Center have shown that an immune regulatory molecule called IL-21 is needed for long-lasting antibody responses in mice against viral infections.
Fast-acting mothers' milk for healthier babies
Human breastmilk responds quickly to protect the child when there is an infection in mothers or babies, according to new international research led by The University of Western Australia.
Non-Hodgkin lymphoma survival doubles since early 1970s
More than half of patients diagnosed with Non-Hodgkin Lymphoma (NHL) are now surviving the disease thanks to improved diagnosis and treatment, according to a new report1 from Cancer Research UK.
Air travel during pregnancy poses no significant risk, say experts
(Medical Xpress)—There is no significant risk directly associated with air travel during pregnancy, even at advanced gestation, says report by the University of Liverpool.