Fat clue to leptin resistance

Triglycerides prevent leptin from crossing the blood-brain barrier | By Stuart Blackman

A paper published in the May issue of Diabetes implicates triglycerides in the mechanism of leptin resistance. These fats, elevated in obesity, are what disrupt the transport of the hormone across the blood–brain barrier (BBB) to its site of action in the hypothalamus, according to the study.

The discovery in 1994 of leptin, an appetite-suppressing hormone produced by fat cells, led to hopes that the peptide could be used to treat obesity pharmacologically. However, it soon emerged that most obese people are resistant to leptin rather than deficient in it. Resistance is associated with loss of function at several stages of the leptin-signaling pathway. Leptin's transport across the BBB is impaired, and there is reduced function of the leptin receptor and its downstream targets, said William A. Banks at the Veterans Affairs Medical Center, St. Louis.

Banks, who led the research, said the idea of a role for triglycerides came about after the team came across a paper showing that leptin transport across the BBB is impaired in starvation as well as in obesity. Bank's team used a brain perfusion method, in which the blood going through the brain vasculature of starved and diet-induced obese mice was replaced with buffer-containing leptin. This restored leptin sensitivity, demonstrating the involvement of a peripherally circulating agent. Banks said the result conjured up “dim memories from old lectures in med school [that] triglycerides go up in starvation.”

Banks' hunch was confirmed when perfusion with milk, which has a high triglyceride content, reduced leptin transport across the BBB, as did treatment with various commercially available triglycerides.

Matthias Tschöp of the University of Cincinnati's Obesity Research Center described the work as a “very exciting finding” that constitutes “major progress” in the field. Tschöp, who was not involved in the study, said that although the triglyceride link had not been considered until now, it seems a “pretty obvious” connection to make, albeit with the benefit of hindsight.

Rockefeller University's Jeffrey M. Friedman, who led the team that discovered leptin, cautioned that a causal link with obesity still needs to be demonstrated. He said an important next step will be to “correlate the effects of triglycerides on blood–brain transport with consistent changes on weight and leptin sensitivity.”

Banks' team also showed that treatment with gemfibrozil, a drug that lowers triglycerides, restored leptin transport in resistant mice. However, Friedman, who was not involved with the study, said that he's unaware of any reported effects of triglyceride-reducing drugs on weight loss. Banks agreed, although he suggested that a data-mining exercise might turn up any such effect that might have been missed. By itself, gemfibrozil is unlikely to have much of an effect against obesity because it is only marginally effective at reducing triglycerides in humans, he said.

Given that leptin resistance is associated with impairments in stages of the leptin-signaling pathway other than transport across the BBB, there is also doubt as to whether triglycerides are the only mediators of leptin resistance. But Banks said that triglycerides do get into the brain, raising the possibility that they are also working at the receptor level. “That's a totally untested area right now, but a very exciting [one],” he said.

The findings also suggest an evolutionary context for leptin resistance, said Banks: When food was harder to come by, triglyceride-mediated resistance was likely to have been an adaptive response to starvation, while its occurrence in obesity might be a nonadaptive consequence of similarly high triglyceride levels.

The molecular mechanism by which triglycerides hamper leptin's passage across the BBB remains to be established. Banks said the fats could be interacting with the leptin directly, with the transporter molecule, or with the way in which the two interact. However, he said, “I'm not sure how to go about answering that question.”