A natural sugar called trehalose offers fasting-like benefits, blocking glucose from the liver and activating a gene that boosts insulin sensitivity. These benefits, observed in mice, suggest new possibilities for treating metabolic syndrome, a cluster of related conditions that includes obesity, diabetes, and fatty liver disease.

The potential benefits of trehalose were highlighted in a recent study of the metabolic response to fasting. The study was conducted at the Washington School of Medicine and focused on the role of the liver.

“Our data suggest that fasting—or giving trehalose with a normal diet—triggers the liver to change the way it processes nutrients, in a beneficial way. If glucose can be blocked from the liver with a drug, it may be possible to reap the benefits of fasting without strictly limiting food,” says Brian DeBosch, M.D., Ph.D., a professor of pediatrics at the Washington School of Medicine.

Details of the study appeared in JCI Insight, in an article titled, “Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPARγ.” According to this article, trehalose activates the Aloxe3 gene, triggering an increase in calories burned, reducing fat accumulation and weight gain, and lessening measures of fats and cholesterol in the blood.

“We demonstrate the epidermal-type lipoxygenase, eLOX3 (encoded by its gene, Aloxe3), is a potentially novel effector of the therapeutic fasting response,” the article’s authors wrote. “We show that Aloxe3 is activated during fasting, glucose withdrawal, or trehalose/trehalose analogue treatment.”

“We learned that Aloxe3 improves insulin sensitivity in the same way that common diabetes drugs—called thiazolidinediones—improve insulin sensitivity,” explains Dr. DeBosch. “And we showed that Aloxe3 activation in the liver is triggered by both trehalose and by fasting, possibly for the same reason: depriving the liver of glucose.”

The researchers found that Aloxe3 in the liver—whether activated by fasting or trehalose—leads the mice to not only make better use of insulin, but to increase calorie burning, raise body temperature, reduce weight gain and fat accumulation—including fat deposits in the liver—and lessen measures of fats and cholesterol in the blood. Further, they found that mice fed an obesity-inducing diet and mice that eat freely and are genetically prone to obesity are protected from metabolic disease if given trehalose in their drinking water.

During fasting, the canonical hepatic response is to shift to mobilize glycogen and oxidize fat from stores to produce glucose and ketone body fuel for the brain and heart. This shift involves transcriptional fasting programming by hepatic transcription factors, including PPARγ coactivator-1α (PGC1α). Ultimately a cascade of signals leads to adipose “browning.” Also, the liver provides energy substrate to the periphery during fasting and promotes peripheral insulin sensitivity for efficient absorption of the next meal.

Fasting’s molecular signaling appears to be amplified by Aloxe3, at least in part, via a PPARγ-dependent mechanism. (The researchers determined that hepatocyte-specific PPARγ deletion reversed the therapeutic effect of hepatic Aloxe3 expression on diet-induced insulin intolerance.)

“We identified Aloxe3 as a potentially novel effector of the hepatic fasting response that is sufficient to augment basal caloric expenditure, and ameliorate insulin resistance, weight gain, and hepatosteatosis,” the article’s authors emphasized. “The rapidly rising prevalence of each of these major public health problems throughout the Western and developing worlds mandates novel therapeutic pathway generation and leveraging thereof. We assert that further interrogation into how hepatic glucose transport mediates the networked adaptive hepatic fasting response will advance the field toward new and effective human therapy against metabolic disease.”

Dr. DeBosch cautioned, however, that trehalose may encounter enzymes in the digestive tract that break it apart, releasing its two glucose molecules, which would be counterproductive. The researchers investigated a similar sugar—lactotrehalose—and they found that it has the same beneficial effects from triggering Aloxe3 but does not break apart as easily.

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