How cellular pathways converge to regulate food intake and body weight

ScienceDaily (July 3, 2012) — 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.

See Also:Health & MedicineObesityDiet and Weight LossFitnessDiseases and ConditionsColon CancerCancerReferenceAppetiteSkeletal muscleBlood sugarInsulin-like growth factor

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."

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Role of cellular protein demonstrated in regulation of binge eating

ScienceDaily (June 20, 2012) — Researchers from Boston University School of Medicine (BUSM) have demonstrated in experimental models that blocking the Sigma-1 receptor, a cellular protein, reduced binge eating and caused binge eaters to eat more slowly.

See Also:Health & MedicineEating Disorder ResearchNutritionDiet and Weight LossMind & BrainEating DisordersNutrition ResearchAlcoholismReferenceBulimia nervosaEating disorderAppetiteOverweight

The research, which is published online in Neuropsychopharmacology, was led by Pietro Cottone, PhD, and Valentina Sabino, PhD, both assistant professors in the pharmacology and psychiatry departments at BUSM.

Binge eating disorder, which affects approximately 15 million Americans, is believed to be the eating disorder that most closely resembles substance dependence. In binge eating subjects, normal regulatory mechanisms that control hunger do not function properly. Binge eaters typically gorge on "junk" foods excessively and compulsively despite knowing the adverse consequences, which are physical, emotional and social in nature. In addition, binge eaters typically experience distress and withdrawal when they abstain from junk food.

The researchers developed an experimental model of compulsive binge eating by providing a sugary, chocolate diet only for one hour a day while the control group was given a standard laboratory diet. Within two weeks, the group exposed to the sugary diet exhibited binge eating behavior and ate four times as much as the controls. In addition, the experimental binge eaters exhibited compulsive behavior by putting themselves in a potentially risky situation in order to get to the sugary food while the control group avoided the risk.

The researchers then tested whether a drug that blocks the Sigma-1 receptor could reduce binge eating of the sugary diet. The experimental data showed the drug successfully reduced binge eating by 40 percent, caused the binge eaters to eat more slowly and blocked the risky behavior.

The abnormal, risky behavior exhibited by the binge eating experimental group suggested to the researchers that there could be something wrong with how decisions were made. Because evaluation of risks and decision making are functions executed in the prefronto-cortical regions of the brain, the researchers tested whether the abundance of Sigma-1 receptors in those regions was abnormal in the binge eaters. They found that Sigma-1 receptor expression was unusually high in those areas, which could explain why blocking its function could decrease both compulsive binge eating and risky behavior.

"These findings suggest that the Sigma-1 receptor may contribute to the neurobiological adaptations that cause compulsive-like eating, opening up a new potential therapeutic treatment target for binge eating disorder," said Cottone, who also co-directs the Laboratory of Addictive Disorders at BUSM with Sabino.

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Cellular Cholesterol Helps Prevent Cancer

When it comes to understanding cholesterol most Americans know there is good cholesterol and bad cholesterol; those who are health conscious often have been hoodwinked into believing they should not eat too many foods that contain cholesterol.  This overly simplistic and inaccurate understanding of cholesterol is required by Big Pharma to con millions of Americans into taking toxic statins to lower their “bad” cholesterol.  The latest study discovers a new role for cholesterol within cells: preventing cancer growth. 

No human being can survive without cholesterol.  It is truly the backbone of your survival, both at a cellular level, and hormonal level, and even a reproductive level.  To understand the context and importance of this new cholesterol discovery allow me to quickly review some basic information about cholesterol.

Good cholesterol (HDL) and bad cholesterol (LDL) are very large molecules made up of fragments of cholesterol, fatty acids, and protein. 

I liken LDL to a UPS truck because its primary function is to transport fat soluble nutrition packages through the waterways of your circulation and all around your body.  It can also double as a police car, using the antioxidants it has on board, to help neutralize problems that are larger than they should be.  It is far from bad; it is required to get nutrition to your cells.  Injured LDL cholesterol Low-density lipoprotein. It is a group of lipids and proteins that allow lipids like cholesterol, triglycerides, and fat soluble nutrients (Vitamin A, D, E , K, Q 10, carotenes) to be transported with the water-based bloodstream. is bad, not LDL in and of itself.

HDL is like a tow truck, hauling spent LDL and hopefully any damaged LDL back to your liver to be recycled or reloaded.

Both HDL and LDL are large molecules in comparison to one molecule of cholesterol, which is a sticky rigid substance about the size of a brick in comparison to an LDL UPS truck.  In fact, fragments of cholesterol are typically transported as one of the packages on the LDL UPS truck to cells in case they need some.

Every cell in your body can make its own cholesterol bricks and can accept cholesterol from a UPS truck delivery.  In fact, cells can even post a UPS call tag so that extra cholesterol can be picked up and taken back to the liver.  Cholesterol is used to prop up the structure of the cell membrane, giving a cell a three dimensional structure.  Most of the cholesterol in your body is these little bricks that help make up a healthy cell.  Without them you would be flat as a pancake.

These cholesterol bricks are also the foundation for your adrenal hormones (managing stress) and sex hormones.  They are required to make vitamin D as well as bile.  They are highly concentrated in your nervous system, making healthy brain cells and are part of the structure of neurotransmitter receptors that are vital to normal brain health.

In other words, having the proper amount of cholesterol is absolutely indispensable to your health and survival.

The current cholesterol lowering fad began in the 1980s with the Mr. Fit study (Multiple Risk Factor Intervention Trial), which followed 350,000 men, age 35-57, for six years and included their total cholesterol as one measurement being followed.  When total cholesterol hit 280, deaths from cardiovascular disease jumped up sharply.  Prior to that number they slowly rose as cholesterol increased. 

However, the point typically ignored by the medical profession and Big Pharma is that the results for all-cause mortality showed a bell shaped curve.  While total cholesterol of 280 or more was bad news as a risk factor, just as many people died whose total cholesterol was less than 140.  These people were not dying of heart disease, rather than infections, cancer, and accidents.  It is rather appalling that the gold standard of statin Class of drugs aka HMG-CoA reductase inhibitors, that are used to lower cholesterol levels by inhibiting the HMG-CoA reductase enzyme that plays a central role in liver function and cholesterol production. prescribing is to push down the total cholesterol to less than 140.

There are always adverse side effects when statins lower LDL cholesterol Low-density lipoprotein. It is a group of lipids and proteins that allow lipids like cholesterol, triglycerides, and fat soluble nutrients (Vitamin A, D, E , K, Q 10, carotenes) to be transported with the water-based bloodstream. too much.  This actually triggers cholesterol starvation in cells, which is anti-survival.  Cell membranes become weaker and age faster.  Nerve cells don’t transmit as well.  Vitamin D levels go down.  Sex drive is a thing of the past.

The new study is the first to discover and explain how low levels of cellular cholesterol, which clearly do occur when LDL levels are forced abnormally low by drugs, cause a break down in cellular regulation of growth which allows for the unchecked growth of cancer.

The researchers discovered that cholesterol within cells binds to something called cholesterol-binding proteins or ORPs.  ORPs were thought to be involved in transport of cholesterol within the cell.  The new research says otherwise, proving that ORPs regulate cell growth.  If cholesterol does not bind to them, because the level is too low, then ORPs go wild and stimulate excessive cell growth.  Cancer must have active ORPs to survive.

The results of this study predict that excessive lowering of cholesterol with statins helps cause cancer, especially in individuals with other risk factors for cancer.  Big Pharma and the FDA don’t want to think about it and gleeful doctors will keep handing out statins like candy.  When will this insanity ever stop?

There is a huge difference in your health between having good cholesterol numbers because you are healthy and having good numbers because you are drugged. 

If you are looking for ways to naturally manage your cholesterol health please review an earlier in-depth article I wrote on this topic, The Five Key Things You Can Do to Lower LDL Cholesterol Healthfully.

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