THE CONNECTION BETWEEN EATING A LOT OF SALT and gaining weight has been a longstanding puzzle. Salt itself contains no calories. If you add salt to a mouse’s diet, it will initially increase its consumption of food but not put on weight. This is partly because salt kick-starts a process in the body that burns calories, which suggests that high-salt intake should lead to weight loss, not weight gain.

But in humans it does just the opposite. High-sodium diets have been associated time and again with obesity and problems with regulating blood sugar and metabolism. Scientists have wondered whether people who eat too much salty food simply have poorer food habits in general, which make them more likely to be obese. But new research may show a more complicated connection.

A pair of studies in 2017 provided details about the effect salt consumption has on mice and humans. In the first, lead author Jens Titze, a kidney specialist who at the time worked at University of Erlangen in Germany (and is now at Duke-National University of Singapore), exposed two groups of 10 Russian cosmonauts, held in isolation, to three different salt intake levels. The more salt they consumed, the hungrier they became.

Titze tried to find the reason for this increased hunger and discovered that a high-salt diet increased levels of glucocorticoid hormones—hormones that break down fat and muscle to free up water for the body. But he still had no idea why. He found his answer in the second study using mice: The process requires a lot of energy, which may be what promoted the mice to eat, on average, 25% more food.

“This shift in metabolism releases more water to dilute the salt,” says Mark Zeidel, a professor of nephrology at Harvard Medical School who wrote an editorial accompanying Titze’s studies in the Journal of Clinical Investigation. “It is similar to the way that camels degrade the fat in their hump when they are deprived of water.”

But even with the increased caloric intake, Titze’s findings implied that a high-salt diet could theoretically cause weight loss, as the body burns more calories to metabolize the higher influx of salt. Recent research by Miguel A. Lanaspa and Richard J. Johnson from the Renal Division at the University of Colorado Hospital Anschutz Medical Campus in Aurora, however, revealed a process that may lead to significant weight gain over the long run.

When Lanaspa and Johnson fed a high-salt solution to their mice, the rodents also had an increased appetite while not gaining weight. That effect lasted only a few months, however. After 13 weeks, the mice gained more weight than mice on a low-salt solution, and they went on to develop obesity, insulin resistance and elevated blood pressure.

Lanaspa and Johnson found that the mice had elevated levels of tonicity-responsive enhancer binding protein (TonEBP), a type of protein that activates the aldose reductase pathway—the only pathway in the body known to create fructose, a kind of sugar. Could the salt-stuffed rodents be producing sugar internally?

To find out, the researchers fed a high-salt solution to genetically modified mice unable to metabolize fructose, which could have caused them to gain weight. Even after 30 weeks on high-salt fare, these mice appeared protected from obesity or metabolic syndrome—implying that it is indeed the internal production of fructose, prompted by salt, that plays a role in long-term obesity.

A related mechanism also seemed to be at work. The mice that couldn’t metabolize fructose ate only about half as many calories as unmodified mice on the high-salt diet. Lanaspa and Johnson believe that internal fructose production eventually causes a reduced sensitivity to leptin, a hormone that signals a mouse—or a person—to stop eating. In this experiment, mice that produced sugar internally also lost the ability to know when they were full.

Whatever the causes, high-salt diets, independent of any other factors, do appear to lead to obesity. Johnson looked at medical records and questionnaires from 13,000 healthy adults at St. Luke’s International Hospital Center for Preventive Medicine in Tokyo and found that, even adjusting for age, body mass index and other qualities, high levels of salt intake made people more likely to develop diabetes and nonalcoholic fatty liver disease regardless of how many calories they consumed.

Lanaspa and Johnson’s research, published recently in Proceedings of the National Academy of Sciences, may help to untangle how salt, despite having no caloric value, leads to added pounds. That answer may lie in a cascade of responses in the body. “It isn’t just the sugar that we eat, but the sugar that we make,” Johnson says.