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DNA-PK Enzyme Drives Middle-Age Weight Gain

June 21, 2017
Scientists have identified an enzyme that promotes weight gain starting in mid-life. A drug that inhibits DNA-PK prevented weight gain in mice, increased fitness levels, and reduced the incidence of obesity and type 2 diabetes. The findings could lead to more effective weight-loss medications.

Interview with Jay H. Chung, MD

Researchers have long been puzzled why so many weight-loss therapies fail, especially in middle age people. Jay H. Chung, MD, was also puzzled by the aging-weight gain paradox. An average adult in America gains 30 pounds from age 20 to 50, even though food intake usually decreases during this period, noted Dr. Chung in a report in NIH Research Matters.1

Dr. Chung, an endocrinologist at NIH’s National Heart, Lung, and Blood Institute (NHLBI), and his associates thus searched for biochemical changes in middle-aged animals (human equivalent of 45 years). Their study appeared on May 2, 2017, in Cell Metabolism.2

The team focused on an enzyme called DNA-dependent protein kinase (DNA-PK). This enzyme is activated by a specific kind of DNA damage, but evidence has been mounting that DNA-PK has functions beyond DNA repair. One such function is in metabolism.

DNA-PK activity lowers the number of mitochondria, shown here, which turn fat into energy to fuel the body.

DNA-PK’s Role in Weight Gain

Dr. Chung and colleagues looked at levels of DNA-PK activity in the skeletal muscles of rhesus macaques and mice. These levels were low over time until middle-age, when they rose significantly, noted the investigators. Further experiments showed that DNA-PK activity promotes the conversion of nutrients to fat and decreases the number of mitochondria. Specifically, Inhibiding HSP90α phosphorylation disrupts HSP90α chaperone function for the AMP-activated protein kinase (AMPK) pathway. Researchers know that fewer mitochondria can promote obesity, slow metabolism, and lower exercise capacity.

The team then theorized that reducing DNA-PK activity might increase the number of mitochondria and promote fat burning. They tested their theory with a drug that inhibits DNA-PK. Mice that received the inhibitor had a 40% decrease in weight gain when fed a high-fat diet. The drug boosted the number of mitochondria in the skeletal muscle, increased the fitness of obese and middle aged mice, and reduced the incidence of obesity and type 2 diabetes.

The team also examined the role of DNA-PK activity in calorie restriction and aerobic fitness, both of which can delay aging and protect against chronic diseases in animal models. Rhesus macaques on a calorie-restricted diet had lower levels of DNA-PK activity in skeletal muscle. Rats selectively bred to be strong runners also had reduced DNA-PK levels in their skeletal muscle—three-fold lower than poor rat runners.

“Our society attributes the weight gain and lack of exercise at mid-life (approximately 30 to 60 years) primarily to poor lifestyle choices and lack of will power, but this study shows that there is a genetic program driven by an overactive enzyme that promotes weight gain and loss of exercise capacity at mid-life,” Dr. Chung said.

How Does Weight Affect Pain?

According to the Centers for Disease Control and Prevention (CDC), nearly two-thirds of US adults are overweight or obese and are at increased risk for musculoskeletal disease.3 Healthcare claims have shown the co-prevalence of pain and obesity to be as high as 30%.4

These high rates of co-occurrence are often associated with a sedentary lifestyle that leads to decreased quality of life, emotional distress, increased disability, and shortened lifespan, according to David Cosio, PhD.5 The medical literature suggests that there is a linear relationship between weight and frequency of musculoskeletal pain. Rates of neck, back, hip, knee, and ankle pain have been found to be significantly higher in obese individuals.6

However, it is unknown whether obesity causes pain or vice versa.7 Obesity is hypothesized to lead to knee and low back pain because of excess mechanical stresses.8.9 Messier et al showed that for each pound of body weight lost, there was a 4-pound reduction in the stress on the knee joints.10

In addition to creating mechanical stress, fat functions much like an organ that secretes chemicals, which affects blood pressure and cholesterol. In fact, adipose tissue is a major source of inflammatory mediators such as cytokines and chemokines.11 Inflammatory markers such as interleukin (IL)-6 and C-reactive protein (CRP) are significantly related to percent of body fat and insulin sensitivity.12 Where the fat is deposited also matters. Visceral abdominal adipose tissue is more metabolically active and releases greater amounts of pro-inflammatory and insulin-resistant substances than other adipose tissue.13

Obesity also has been associated with thoracic spine, neck, and upper extremity pain. When it is present in conditions such as fibromyalgia, migraines, and headaches, obesity also exacerbates pain due to its pro-inflammatory state.14 Chronic pain may also result in obesity because it leads to physical inactivity, especially in the elderly.15,16 Thus, the reciprocal should be true—weight loss can help reduce chronic pain. For example, one study found that more than a 10% loss of body weight resulted in a 50% decrease in knee osteoarthritis in patients diagnosed with obesity (body mass index >35).17

The findings of the new study could lead to the development of a new type of weight-loss medication, which will have prevent the development of metabolic syndrome and chronic pain conditions. However, the researchers caution, DNA-PK inhibitors have yet to be tested in humans. Middle-aged people who are fighting obesity should continue to reduce calories and boost exercise.

The study was funded by the NIH’s National Heart, Lung, and Blood Institute (NHLBI) and Office of the Director (OD); Korea Health Technology R&D Project; Korea Health Industry Development Institute; and Ministry of Health & Welfare of the Republic of Korea.

 

Last updated on: June 20, 2017
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