Led by Dongsheng Cai, an assistant professor of physiology at the UW School of Medicine and Public Health, the researchers looked specifically at the hypothalamus--the brain structure responsible for maintaining a steady state in the body--and for the first time found that a cell-signaling pathway primarily associated with inflammation also influences the regulation of food intake. Stimulating the pathway led the animals to increase their energy consumption, while suppressing it helped them maintain normal food intake and body weight.

The research stems from recent explorations into the problem called metabolic inflammation, a by-product of too much food or energy consumption. Unlike the classical inflammation typically observed in infections, injuries and diseases such as cancer, the metabolic inflammation seen in obesity-related diseases is much milder, doesn't lead to overt symptoms or cause tissues damage.

Metabolic inflammation is a chronic, low-grade condition consisting of inflammatory-like responses at the molecular level. It has many downstream consequences, says Cai. It causes cellular dysfunction, which can decrease the regulation of several physiological processes, including metabolism.

Scientists believe that metabolic inflammation may be at the core of many chronic, obesity-related metabolic disorders that are so common today, he adds.

Cai and his team zeroed in on NF-kappaB, a protein complex that can be activated specifically by IKKbeta to induce inflammatory reactions in many cell systems.

In earlier studies at Harvard, Cai and colleagues found that the pathway interrupted sugar, fat or protein metabolism in tissues where metabolism typically takes place--liver, fat and skeletal muscle. Feeding mice high-sugar and high-fat diets activated the pathway in these tissues.

Once he arrived at the SMPH three years ago, Cai began to consider whether metabolic inflammation might affect higher-up players in the central nervous system, particularly the hypothalamus. This brain structure is a critical master regulator of appetite and energy balance, and also controls metabolism in the peripheral tissues he had studied before. But nobody knew how the hypothalamus might contribute to the development of metabolic diseases such as obesity and diabetes.

We wanted to learn whether the pathway or pathways underlying metabolic inflammation could affect metabolism regulators in the central nervous system,╙ he says.

In the current study, Cai and his team found first that IKKbeta/NF-kappaB does indeed exist in specific neurons in the hypothalamus. The pathway is much more abundant in the hypothalamus than in peripheral tissue, and it normally remains inactive in the brain.

The researchers next showed that over-nutrition through high-fat diet feeding activates IKKbeta/NF-kappaB, specifically in neurons in the hypothalamus.

╥When we knocked out the IKKbeta gene to suppress NF-kappaB activity in these neurons, the animals were significantly protected from energy over-consumption and obesity development, Cai says.

The researchers also examined a cell component called the endoplasmic reticulum (ER), shown recently to be involved in metabolic diseases involving over-nutrition, to see if it might play a role in linking over-nutrition to activate IKKbeta/NF-kappaB in the hypothalamus.

At the intracellular level, when the ER is challenged with over-nutrition, this leads to ER stress, which can push the IKKbeta/NF-kappaB pathway to an active state, although the involved reactions could be quite complicated, Cai says.

In several experiments, the researchers found that ER stress caused by over-nutrition activated IKKbeta/NF-kappaB in the hypothalamus. Suppressing ER stress in the central nervous system significantly preserved normal regulation of food intake and prevented obesity.

Cai says there╒s still a lot of work to be done. His group has begun studying IKKbeta/NF-kappaB connections to other pathways and regulations in the hypothalamus.

The ultimate goal will certainly be to identify a selective and effective suppressor of the pathway to target related neurons, he says.

But Cai continues to look at the big picture, seeking answers to questions such as: ╥How does the environment connect to the genetics that seem to underlie the obesity epidemic? What are the key steps that have led to the dramatic rise of diabetes in the past three decades? and Why can╒t the body adjust to changes that have occurred in the way people eat and what they eat?

About Obesity

Obesity is a condition in which the natural energy reserve, stored in the fatty tissue of humans and other mammals, exceeds healthy limits. It is commonly defined as a body mass index (BMI) (weight divided by height squared) of 30 kg/m² or higher.

Mortality is increased in obesity, with a BMI of over 32 being associated with a doubled risk of death.  Central obesity (male-type or waist-predominant obesity, characterized by a high waist-hip ratio), is an important risk factor for the metabolic syndrome, the clustering of a number of diseases and risk factors that heavily predispose for cardiovascular disease. These are diabetes mellitus, Type 2 diabetes mellitus, high blood pressure, high blood cholesterol, and triglyceride levels (combined hyperlipidemia).

Apart from the metabolic syndrome, obesity is also correlated with a variety of other complications. For some of these complaints, it has not been clearly established to what extent they are caused directly by obesity itself, or have some other cause (such as limited exercise) that causes obesity as well. The affected health conditions include but are not limited to:

• Cardiovascular: congestive heart failure, stroke, enlarged heart and its associated arrhythmias and dizziness, varicose veins, and pulmonary embolism
• Endocrine: type 2 diabetes mellitus, insulin resistance, polycystic ovarian syndrome (PCOS), menstrual disorders, and infertility
• Gastrointestinal: gastroesophageal reflux disease (GERD), fatty liver disease, cholelithiasishernia, and colorectal cancer
• Renal and genitourinary: erectile dysfunction, urinary incontinence, chronic renal failure, hypogonadism (male), breast cancer (female), uterine cancer (female), stillbirth
• Integument (skin and appendages): stretch marks, acanthosis nigricans, lymphedema, cellulitis, carbuncles, intertrigo
• Musculoskeletal: hyperuricemia (which predisposes to gout), immobility, joint pain, osteoarthritis, low back pain
• Neurologic: stroke, meralgia paresthetica, headache, carpal tunnel syndrome, dementia, idiopathic intracranial hypertension
• Respiratory: obstructive sleep apnea, obesity hypoventilation syndrome, asthma
• Psychological: depression, low self esteem, body dysmorphic disorder, social stigmatization
• Erectile Dysfunction 

About Heart Disease

• Arrhythmias. Irregular, or abnormally fast or slow, beating of the heart. The heart beat is controlled by electrical impulses. When the timing or frequency of these electrical impulses are disrupted, arrhythmias develop. Some arrhythmias are quite serious. An example is ventricular fibrillation, a severely abnormal heart rhythm that causes death unless treated right away by providing an electrical shock to the heart (called defibrillation). Others are less severe but can develop into more serious conditions over time. A particular concern is atrial fibrillation. Atrial fibrillation is rapid, irregular beating of the upper chambers of the heart. The chambers can quiver instead of beating in a regular pattern. Blood is not fully pumped out of them and may pool and clot.
• Cardiomyopathy. A weakening of the heart muscle or a change in heart muscle structure. It often results in inadequate heart pumping or other heart function abnormalities. These can result from various causes, including prior heart attacks, viral or bacterial infections, and others.
• Congenital Heart Disease. Malformations of heart structures, present during pregnancy or at birth. These may be caused by genetic factors or by adverse exposures during pregnancy. Examples include holes in the walls that divide the heart chambers, abnormal heart valves, and others. Congenital heart defects can disrupt the normal flow of blood through the heart. Congenital heart defects are the most common type of major birth defect.
• Coronary Heart Disease (CHD)/ Coronary Artery Disease (CAD). Coronary artery disease (CAD), also called coronary heart disease (CHD) is a narrowing of the small blood vessels that supply blood and oxygen to the heart. CAD is the most common type of heart disease. CAD is the leading cause of death in the United States for men and women. According to the American Heart Association, more than 15 million people have some form of the condition. Coronary artery disease is caused by any problem with the coronary arteries that keeps the heart from getting enough oxygen- and nutrient-rich blood. The most common cause is atherosclerosis which occurs when fatty material and a substance called plaque builds up on the walls of your arteries. This causes them to get narrow. As the coronary arteries narrow, blood flow to the heart can slow down or stop The lack of sufficient blood is called ischemia, so coronary artery disease is sometimes called ischemic heart disease. The lack of blood flow can cause chest pain (stable angina), shortness of breath, irregular heart beats, called arrhythmias, and other symptoms.  Over time, CAD can weaken the heart muscle and lead to heart failure, a serious problem where the heart cannot pump blood the way that it should.
• Heart Attack. A heart attack, also called a myocardial infarction may occur when blood supply to the heart is severely reduced or completely blocked. When blood flow is restricted the heart muscle cells do not receive enough oxygen and begin to die. The more time that passes without treatment to restore blood flow, the greater the damage to the heart. This damage can cause irregular heart rhythms or even sudden cardiac arrest or stopping of the heart beat. Death can result. Coronary artery disease is the chief underlying cause of a heart attack. A less common cause of a heart attack is a severe spasm of a coronary artery that reduces the blood supply to the heart.
• Heart Failure. This may also be called congestive heart failure or chronic heart failure. Heart failure is a condition where the heart cannot pump enough blood and oxygen to meet the needs of other body organs. Heart failure does not mean that the heart has stopped, but that it cannot pump blood the way that it should. Heart failure is a serious condition. There is no cure for heart failure at this time, except a heart transplant. Once diagnosed, medicines are needed for the rest of the person's life. See our heart failure fact sheet.
• Peripheral Arterial Disease (PAD). Hardening of the arteries that supply blood to the arms and legs. PAD is usually the result of atherosclerosis, the buildup of plaque and narrowing of the arteries. Blood flow and oxygen to the muscles in the arms and legs can be reduced or even fully blocked. Painful leg muscles, numbness, swelling in the ankles and feet, and weak pulse in the feet are some of the signs and symptoms of PAD.
• Rheumatic Heart Disease. This condition is damage to the heart valves and other heart structures due to inflammation and scarring caused by rheumatic fever, which occurs from streptococcal infection. Heart disease is an umbrella term for a number of different diseases affecting the heart. Heart disease is a number of abnormal conditions affecting the heart and the blood vessels in the heart.

About Diabetes

Type 2 diabetes is also referred to as non-insulin dependent diabetes mellitus (NIDDM), or adult onset diabetes mellitus (AODM). Type 2 diabetes affects nearly 21 million in the United States and nearly 200 million people worldwide.

Type 2 diabetes is characterized by high levels of blood sugar, caused by the body's inability to utilize insulin to move blood sugar into the cells for energy. In type 2 diabetes, patients can still produce insulin, but do so relatively inadequately for their body's needs, particularly in the face of insulin resistance as discussed above. In many cases this actually means the pancreas produces larger than normal quantities of insulin.

Diabetes is a major cause of heart disease and stroke, as well as the most common cause of blindness, kidney failure and amputations in U.S. adults.