GDF15, Morning Sickness & Mitochondrial Stress | Stephen O'Rahilly | Episode 311

When we think about obesity and we think about hunger and satiety generally, you know, people often talk about insulin in the context of, you know, fat storage and how it's affected by diet and people often become insulin resistant.

There's a very close correlation between metabolic dysfunction and insulin resistance, including in obesity.

So even in people that don't have the rare genetic condition where they're not producing leptin, we talk about insulin resistance, but there's also leptin resistance.

So can normal people can become resistant to the effects of leptin?

I mean, that's almost by definition, if you're fat and you have high circulating levels of leptin, then by definition, in some ways, you're leptin resistant because you're not suppressing your food intake to go back down to a normal body weight.

I mean, there are lots of people who debate the term leptin resistance.

Martin Myers, for example, an expert in the University of Michigan, thinks it's a terrible term and we should never use it.

It makes us blind to what – he thinks it's just a range of normal biology.

But there's no doubt that there are individuals who are truly leptin resistant.

I mean there are plenty of people now defined with leptin receptor mutations and homozygous and they look like people who are totally deficient and they don't respond to injected leptin.

But yeah, I think that it's not unreasonable to think about leptin resistance.

And then if you think, could we be smart enough to come up with drugs that overcome leptin resistance and become leptin sensitizers? Might it be possible to develop something that could be a leptin sensitizer? Yeah.

And that's not crazy.

I'm aware of several biotech companies looking for leptin sensitizers.

But in some ways, are the GLP-1 agents leptin sensitive? They are because they make you get less leptin.

your leptin levels drop.

And my guess would be if you took people who had been rendered normal weight by giving them GLP-1 and you gave them a shot of leptin, they'd probably respond better to that leptin.

So almost anything that makes you thinner will in some way leptin sensitize you.

So leptin, it's a...

It's tied to satiety and hunger.

It's literally like a fat.

It's a fat to ride.

It's telling your brain how much body fat you have in essence.

Yeah.

I mean, it's more, it's broader than that and more important than that in some ways, because basically you can imagine, I do see it more as the starvation hormone.