The Role of Leptin in Obesity, Type 2 Diabetes, Other Metabolic Conditions

At the American Diabetes Association's 78th Annual Scientific Session, MD Mag spoke with Murray Stewart, MD, the executive vice president and head of research and development at Novelion Therapeutics, about his research into the hormone leptin—a major player in appetite and metabolism, with much that's still misunderstood about it—presented at the annual meeting.

In addition to speaking about how that's led to most of his research into the hormone, Stewart spoke about where the medical community's understanding of leptin has come since the 1990s, and whether or not it has positive benefits and for which patients. He also noted the need for a better understanding of its relationship with type 2 diabetes and other metabolic conditions, many of which may be driven by its mechanism of action.

Murray Stewart, MD:

We know that people who have no leptin at all, [which is] very rare—that there are some children who've got congenital leptin deficiency. This was identified in the 1990s. Those children, after a few years, present with massive obesity. They're very hungry, they gain weight, they have infections. Those [are] individuals, who, if you treat them with leptin, it helps them lose weight.

People then thought, “Ah, this hormone is a satiety hormone that treats hunger,” and therefore it can work in all obese people. When it didn't work in everyone who was obese, everyone said, “Oh, I don't understand that,” and they put it on the shelf. But, we're coming back with this thinking [that], well, if it worked with people with no leptin, maybe it works in people who have just a little bit of leptin, and it's driving their hunger. So, it's a straightforward hypothesis that leptin is a hormone—if you have enough leptin, giving leptin really wouldn't make much difference, but if you have low leptin, it will work. We're evolving the story from leptin’s not for everyone, but for those people with minimal or low leptin levels.

In parallel to doing this work, we need to identify leptin levels in [patients that are] obese and have type 2 [diabetes] and find out whether low leptin metabolic disturbance [is common and] how common it is. We know by the leptin levels we looked at that it's 1% to 2% because we're targeting people with low leptins. But we don't know what these people look like. Future work will be taking people who have low leptin and obesity and comparing them to people with high leptin and obesity and seeing if these people—rather than their leptin levels—maybe look differently.

We believe that leptin, because it controls metabolism, that the low leptin people may have, or may be more prone to, diabetes and other metabolic conditions that are driven by the mechanism of leptin’s action.

Most people think leptin is associated with lipodystrophy, so if you have no fat, you don't secrete leptin. The main treatment for leptin, [what] it's approved for, is lipodystrophy, so people with generalized lipodystrophy—who have no fat. The odd thing [then,] is, well why would it work in people who have lots of fat? The key thing is we have people who are obese and overweight, and there's a small population that is not producing leptin. Most people think that people who are obese have lots of leptin, and the reason leptin isn’t working is because they're resistant to leptin. The key thing about this poster [presentation at ADA] is there are some people who are obese who have low leptin, and they may benefit from leptin [treatment].

Transcript edited for clarity.

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