Blood thinner's ability to boost fat burning could inspire new obesity therapies

Brown fat is considered the good fat, because, unlike energy-storing white fat, it burns calories. So expanding brown fat tissue or boosting its activity holds therapeutic promise to treat obesity.

Now, a research team led by scientists at the University of Bonn in Germany has identified a molecular mechanism by which brown fat increases energy expenditure and showed how a blood thinner drug may stimulate that process in mice.

Dying brown fat cells release a specific pattern of molecules filled with purine metabolites, the team found. Among them, the purine inosine appeared to drive energy burning in neighboring healthy fat cells, the researchers described in a new study published in Nature.

In mice, treatment of inosine led to a protein expression profile in brown fat cells that indicated enhanced heat production. Inosine also induced “browning” of mature white fat cells.

As for whole-body energy expenditure, injection of inosine in mice led to a significant increase in oxygen consumption, which suggested a higher metabolic rate. More importantly, mice fed a high-fat diet and treated with inosine gained significantly less weight than control mice did even though food intake and gastrointestinal movement were similar.

In already obese mice, injection of inosine for 26 days significantly lowered the animals’ bodyweight as a result of reduced fat mass compared with control mice from Day 7 onward, the team reported.

The scientists further examined the mechanism behind the release of inosine. They found that the protein ENT1 regulates inosine levels in fat cells. ENT1 appeared to be involved in inosine shuttling as fat cells without the protein took in less inosine, leaving more in the extracellular space to potentially exert the energy-burning effect.

Indeed, in a mouse model with ENT1 knocked down in their fat tissues, the rodents gained less weight while on a high-fat diet compared with control animals and showed an improved glucose tolerance.

The researchers then tried to inhibit the inosine transporter with a drug—specifically, the blood thinner dipyridamole, which is known to block ENT1.

Treatment of dipyridamole in mice led to increased oxygen consumption, although the drug alone didn’t seem powerful enough. In a low temperature condition, the dipyridamole-treated animals had significantly larger brown fat mass but reduced white fat tissue weights compared with control mice.

The mouse findings about inosine and ENT1 were largely similar in human fat cells in lab tests, including the “browning” of white fat after reduction of ENT1, the team showed.

Interestingly, analysis of a human genomic database revealed that some people bear a genetic variant that cripples ENT1. Strikingly, in a cohort of about 900 people with available data, the variant was significantly associated with lower average body mass index. Carriers of the mutation had 59% lower odds of obesity, the team found.

Promoting brown fat has been an attractive strategy being explored in obesity research. A team led by Harvard University previously used CRISPR-Cas9 to engineer human white fat to activate expression of the protein UCP1, which is involved in heat production by fat tissue. When transplanted with the engineered brown-like cells, mice gained less weight when fed a high-fat diet compared to those receiving white control cells.

In a Nature Metabolism study published last year, scientists at the Joslin Diabetes Center described smooth muscle cells expressing a protein receptor called Trpv1—which is known to help sense pain and temperature—as a new source of brown fat cells. That team proposed that targeting these cells to increase numbers of brown fat cells might be a plausible therapeutic approach against obesity.

The University of Bonn team now suggests the same for inosine and ENT1. Dipyridamole could serve as a starting point, the team argued, given that it’s already approved for cardiovascular disease.

“[T]argeting ENT1/increasing inosine might be an alternative or synergistic approach for future anti-obesity therapies,” the scientists wrote in the study.