Why is leptin ignored in obese people and animals?

As many of you know, leptin is the signal released from fat cells that relays a message to the brain that the fat cells are 'full' and it's time to stop eating. It has also been discovered that leptin works directly on the fat cells themselves, decreasing their fat-storing ability.

Mice (and people) who have a genetic deficiency of leptin get very, very obese, and giving them a synthetic leptin causes them to rapidly slim down. This generated huge interest in the drug industry about 10 years ago, but it turns out that leptin deficiency is very rare in humans and most 'normal' obese individuals, as well as those with PWS, have very high levels of leptin circulating in their blood. The question then became, if they have high levels of leptin, why doesn't the brain or the fat cells get the message to stop eating (why is there leptin resistance??). There are probably a number of reasons, including the fact that several other hunger regulating hormones have since been discovered and also play a role, but this article explores the basis of leptin resistance.

In this case, the authors are looking at why the fat cells themselves stop responding to leptin. We know that lean rats lose fat from adipocytes (fat cells) when leptin is administered, but obese rats do not. This paper explored why the fat cells of rats eating a high fat diet are able to store fat at the same time they are managing to secrete leptin at concentrations that should inhibit production and storage of fat. They find that two things that happened to the fat cells of the rats fed a high fat diet and within days, they started expressing lots of a protein that blocks the action of leptin. To add to the problem, within weeks of being on a high-fat diet, their fat cells stopped making the receptor for leptin - another mechanism to keep leptin from working. So even though leptin was being churned out by the fat cells, the message was ignored because the receptor was gone. The authors conclude that a high-fat diet causes resistance to leptin signaling in adipocytes. Further, the increase in size and number of fat cells that causes obesity can occur only if the adipocytes manage to ignore the leptin concentrations to which they are exposed. They further speculate that a period of starvation of patients might reduce such a blockade and allow a beneficial response to leptin therapy in obese patients.This better understanding of how leptin resistance occurs may lead to new therapeutic agents to allow the leptin to be "heard" by the brain and the fat cells.

Fat storage in adipocytes requires inactivation of leptin's paracrine activity: Implications for treatment of human obesity Wang M-y, Orci L, Ravazzola M, Unger RH. PNAS 2005 102: 18011-18016

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Topics: Research

Theresa Strong

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Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.

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