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22 April 2005
Faulty Biological Clock Leads To Weight Gain 
Researchers at Northwestern University and the Howard Hughes Medical Institute have identified wide-ranging and significant molecular and behavioral changes in mice that have a faulty circadian system. The circadian system is sometimes referred to as the biological clock as it controls the timing of processes and metabolic events in the body. The changes observed in the faulty-clock mice, when seen in humans, can lead to cardiovascular disease and type 2 diabetes. The study, appearing in Science Express, suggests a possible new angle for understanding and eventually preventing and treating obesity and related disorders in people. The mice in question have defective 'clock' genes that control daily rhythms in the brain and throughout the body, including sleeping and eating. Researchers have shown that the 'clock' gene and a half-dozen other proteins run 24-hour oscillating clocks in most cells in the body and in a specific part of the brain that controls appetite and wakefulness. The 'clock' mutant mice lost both their alarm clocks and their internal dinner bells. Mice typically sleep during the day and then eat a meal at the beginning and at the end of their active nocturnal day, akin to breakfast and dinner. Instead, the 'clock' mutant mice skipped their meals, stayed awake far into the usual rest time, and snacked often. In repeated measurements, the researchers found signs of further trouble emerging in the mice's early adult months. The circadian-challenged mice developed high cholesterol, high triglycerides, high blood sugar, low insulin, bloated fat cells, and lipid-engorged liver cells. Some of these changes appeared to be independent of the weight gain, co-author Joseph Bass said. The researchers found changes in the key proteins in the hypothalamic region of the brain that manages feeding, energy balance, and sleep-wake regulation. They suspect the metabolic changes are caused more directly by misregulated genes in various tissues normally controlled by the 'clock' gene, rather than by the effects of the weight gain. "It's like an orchestra," said Bass. "The tissues important in metabolism have to be conducted properly. But in the 'clock' mutant, each tissue plays to its own beat, which creates cacophony at the biological level that sets up the animal for obesity and metabolic disregulation. Timing is critical to keep the metabolic symphony in tune," he said. "It don't mean a thing if it ain't got that swing," Bass concluded.
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