A new study published in Obesity found that mice that eat a high-fat diet (HFD) cause aldose reductase (AR) activity, expression, and senescence of adipocytes in subcutaneous adipose tissue (scAT).

According to the study’s corresponding author, Ravichandran Ramasamy, the findings show that “aldose reductase gene expression increases in scAT of obese humans and mice, and that an inhibitor of aldose reductase attenuates weight gain, reduces adipocyte senescence, and promotes lipolysis in HFD-fed mice.”

“These data,” the author adds, “pave the way for testing these inhibitors as therapeutic adjuncts in treating patients with obesity.“

All of the male mice used in the study were given unrestricted access to food and drink as well as 12-hour cycles of light and darkness. AR-knocked-out mice and their wild-type littermates were employed in the experiment.

All of the mice used in the experiments were divided into treatment groups at random. Regarding food, eight-week-old mice were fed an HFD (60 percent of calories from lard) or conventional chow (13 percent of calories from fat) for 12 weeks and the senescence marker was measured.

In specific trials, after 11 weeks of HFD feeding, the aldose reductase inhibitor (ARI) Zopolrestat (Zop), 2.5mg/kg body weight, or a vehicle (potassium bicarbonate buffer used to dissolve Zop), was provided once daily via oral gavage for three weeks. Measurements of sorbitol and AR activity were conducted as previously reported.

The genotype, diet, and particular treatments were hidden from the experimenters. Data from the experiments were examined after the studies by experimenters who were not aware of the experimental groups or treatments. Researchers collected cDNA samples of subcutaneous fat from fasting lean and fasted obese participants for use in human subjects.

The results showed that when mice were fed HFD, there was a significant rise in AR and the senescence marker Cdkn2a expression in all tissues as compared to animals fed chow. After a four-hour fast, measurements of glycerol, non-esterified free fatty acids (NEFA), and triglycerides from the plasma of these mice showed that the HFD-fed animals had considerably greater NEFA levels than the chow-fed mice. Studies on human people with obesity and cDNA samples revealed higher expression of AR and senescence markers.

When scAT fat pads were removed from mice fed on the HFD compared to mice fed on regular chow, measurements of the released NEFA showed a roughly 50% reduction in 3-agonist CL 316,423 (CL)-stimulated lipolysis; no diet-dependent variations in baseline lipolysis were seen.

Reduced senescence and enhanced lipolysis in scat were seen in AR deficient mice and ARI treated mice on HFD. Together, these findings show evidence of accelerated senescence and faulty CL-stimulated lipolysis in obese mice, both of which are partially regulated by AR.

“This is an important discovery, and the data is compelling,” comments AdventHealth Senior Vice President and Chief Scientific Officer Steven R. Smith.

“Today, we don’t have good medicines that target dysfunctional adipose tissue. 

“I’m very excited by this work; these findings should compel scientists to find drugs that impact this novel pathway and could be used to treat both obesity and diabetes.”

Image Credit: Getty

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