Faulty Body Clock Leads to Obesity and Diabetes

April 26, 2005

Faulty Body Clock Leads to Obesity and Diabetes

EVANSTON, Ill.—Obesity and diabetes in both adults and children are rising at alarming rates, and a wide range of culprits—super-sized food portions, lack of exercise due to television and computers, suburban sprawl, l oss of gym classes, high-fat and fast foods, sugar-laden drinks, and psychological trauma—have been blamed.

Now researchers from Northwestern University and Evanston Northwestern Healthcare (ENH) have pinpointed something deep within the brain and other tissues that plays an important role in the struggle to maintain a healthy weight: the body’s 24-hour internal clock. The research team, led by an endocrinologist and a circadian rhythms expert, has shown that a faulty or misaligned body clock, which regulates both sleep and hunger, can wreak havoc on the body and its metabolism, increasing the propensity for obesity and diabetes.

The findings appeared April 21 in the online issue of the journal Science.

“Just as there is a mechanism that makes the heart beat, there is a clock that functions in many different parts of the body to regulate many different systems,” said Joseph T. Bass, MD, PhD, senior author and assistant professor of medicine and of neurobiology and physiology at Northwestern and head of the division of endocrinology and metabolism at ENH.

“We don’t know too much about how clocks control eating and metabolism in normal individuals, but now we have shown that weight gain and abnormalities in metabolism, including diabetes, result if this internal timepiece is malfunctioning. The body clock is clearly controlling the elaborate brain signaling system that regulates appetite.”

“We’ve demonstrated that an animal model with a known circadian disregulation—a mouse with a mutant Clock gene and thus an imprecise body clock—has metabolic problems, at least obesity and signs of the metabolic syndrome,” said circadian rhythm expert Fred W. Turek, PhD, lead author on the paper and professor of neurobiology and physiology in Northwestern’s Weinberg College of Arts and Sciences.

“This provides new genetic evidence that physiologic outputs of the biological clock, sleep, and appetite are interconnected at the molecular and behavioral levels, yielding implications on the role of internal biological timing in optimizing strategies to reduce and sustain weight loss resulting from both medical and lifestyle modifications.”

The research team also includes Joseph S. Takahashi, PhD, Walter and Mary Elizabeth Glass Professor in the Life Sciences and a Howard Hughes Medical Institute investigator at Northwestern, who led the team that cloned the first mammalian circadian gene, Clock, in 1997. This discovery provided the genetic model critical to this study.

The scientists exposed mice to regular and high-fat diets and compared the response of the mutant animals with the response of the normal animals. They discovered that the animals with the Clock mutation were unable to regulate their body weight in the presence of either diet. The effect of the Clock mutation on body weight in animals fed a regular diet was similar in magnitude to the effect of a high-fat diet in normal mice. When the Clock mutant animals were fed a high-fat diet, the combined effect of diet plus mutation led to the most severe alteration in body weight and changes in metabolism. The obese mice showed metabolic abnormalities in insulin secretion and the ability of the liver to handle sugar.

Obesity is associated with metabolic and cardiovascular disorders often referred to as the metabolic syndrome, which increases an individual’s risk of developing a serious disease, said Drs. Bass and Turek. In addition to excess body weight, factors include high blood pressure, high insulin levels, one or more abnormal cholesterol levels, and, at the whole-animal level, an inability to expend excess calories consumed. Robert H. Eckel, MD, an author on the Science paper and professor of medicine at the University of Colorado at Denver, and his colleagues found the Clock mutant animals had reduced energy dissipation despite positive energy balance, compounding the obesity phenotype in these animals.

“Our findings lead to provocative questions that require further investigation,” said Dr. Bass. “Is it possible that sleep loss or a change in circadian rhythms might exacerbate problems in regulating appetite? It may be a question of not only how much you eat but what time of day you eat and how that affects the body. Are you eating at a time of day when your system is internally aligned to metabolize the food?”

Approximately 18 million people in the United States have diabetes and nearly two-thirds of adults are overweight, which includes 30 percent who are obese. Together, diabetes and obesity result in almost 200,000 deaths annually and exert a devastating social and economic toll due to complications including blindness, kidney failure, heart disease, and stroke.

Biological clocks function in the brain as well as lung, liver, heart, and skeletal muscles. They operate on a 24-hour, circadian (Latin for “about a day”) cycle that governs functions like sleeping and waking, rest and activity, fluid balance, body temperature, cardiac output, oxygen consumption, and endocrine gland secretion.

“The body clock regulates the time we go to bed, the time we get up, and the time we get hungry—these are biological principles, not psychological factors,” said Dr. Bass. “This internal drive is a fundamental system that is important to health.”

In addition to Drs. Bass, Turek, Takahashi, and Eckel, other authors on the Science paper are Corinne Joshu, Akira Kohsaka, Emily Lin, Ganka Ivanova, Erin McDearmon, Aaron Laposky, Sue Losee-Olson, and Amy Easton, from Northwestern University, and Dalan R. Jensen, from the University of Colorado at Denver.

The research was supported by the National Institutes of Health under grants AG18200, DK02675, AG11412, HL75029, HL59598, and DK26356.