08:29pm Saturday 19 August 2017

Liver Fat Gets a Wake-Up Call That Maintains Blood Sugar Levels, According to Penn Study

Insulin resistance occurs when the body does a poor job of lowering blood sugars. Typically, patients with obesity and type 2 diabetes have fatty livers, and the dogma in the field, says Lazar, is that the fatty livers contribute to the insulin resistance and diabetes in a vicious cycle. These findings are “a clear counterexample to this thinking,” he says.

The researchers observed that the extra fat in the liver did not cause insulin resistance because it was sequestered in tiny lipid droplets inside individual liver cells, coated by a specific protein. The metabolites that would otherwise be used by the body to make glucose were re-routed to make fat, leading to reduced glucose in the bloodstream. The advantage of the lower blood sugar is tempered by the excess liver fat, which can lead to problems of its own, including liver failure.

Cells of high-fat-diet-induced fatty livers in wild-type mice were characterized by larger lipid droplets, but liver-specific HDAC3 knockout mice on a high-fat diet were characterized by smaller lipid droplets, even though the total lipid content increased versus the wild-type mice.

Why would the body have this re-routing process in the first place? The team looked to the circadian rhythm of the nocturnal mice for answers. When inactive during the day, mouse HDAC3 migrates to genes to turn off fat synthesis. This allows metabolites to make glucose for fueling the sleeping body. When waking, during the night, the mouse body makes a metabolic switch, anticipating the intake of food, and turns on fat synthesis for energy storage. The on-and-off cycle of HDAC3 is directly regulated by the internal circadian clock, and the system falls apart when HDAC3 is deleted.

The findings suggest that the cordoning off of lipids of the liver in many, tiny coated droplets helps to manage insulin resistance in the body. And, the findings cement the fact that HDAC3 is pivotal in integrating signals from the internal body clock to coordinate metabolism, especially in the liver, notes the first author Zheng Sun, PhD, postdoctoral fellow in the Lazar lab.

The findings demonstrate that fat itself is not necessarily all bad. “It matters a lot how fat is handled and stored,” notes Lazar. “It also highlights the importance of complying with our internal circadian clock. For example, since our body does not anticipate food at night and is preparing to generate more glucose, night-time eating is likely to shoot up blood sugar and thus may contribute to diabetes.”

The work was funded in part by National Institute of Diabetes and Digestive and Kidney Diseases (R37 DK43806; P01 DK49210; R01 DK40936; R01 DK075017); the Cox Institute of Medical Research; and the JPB Foundation.

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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.


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