Lipocalin-2 Could Be Used as Potential Treatment for Obesity

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A research team reports that hormone that can suppress food intake and increase the feeling of fullness in mice has shown similar results in humans and non-human primates. The study “Lipocalin-2 is an anorexigenic signal in primates” appears in eLife.

“In the mouse, the osteoblast-derived hormone Lipocalin-2 (LCN2) suppresses food intake and acts as a satiety signal. We show here that meal challenges increase serum LCN2 levels in persons with normal or overweight, but not in individuals with obesity,” write the investigators.

“Postprandial LCN2 serum levels correlate inversely with hunger sensation in challenged subjects. We further show through brain PET scans of monkeys injected with radiolabeled recombinant human LCN2 (rh-LCN2) and autoradiography in baboon, macaque, and human brain sections, that LCN2 crosses the blood-brain barrier and localizes to the hypothalamus in primates. In addition, daily treatment of lean monkeys with rh-LCN2 decreases food intake by 21%, without overt side effects.

“These studies demonstrate the biology of LCN2 as a satiety factor and indicator and anorexigenic signal in primates. Failure to stimulate postprandial LCN2 in individuals with obesity may contribute to metabolic dysregulation, suggesting that LCN2 may be a novel target for obesity treatment.”

“LCN2 acts as a signal for satiety after a meal, leading mice to limit their food intake, and it does this by acting on the hypothalamus within the brain,” explains lead author Peristera-Ioanna Petropoulou, PhD, who was a Postdoctoral Research Scientist at Columbia University Irving Medical Center at the time the study was carried out, and is now at the Helmholtz Diabetes Center, Helmholtz Zentrum München in Germany.

“We wanted to see whether LCN2 has similar effects in humans, and whether a dose of it would be able to cross the blood-brain barrier.”

The team first analyzed data from four different studies of people in the U.S. and Europe who were either normal weight, overweight, or living with obesity. The people in each study were given a meal after an overnight fast, and the amount of LCN2 in their blood before and after the meal was studied.

The scientists found that in those who were of normal weight, there was an increase in LCN2 levels after the meal, which coincided with how satisfied they felt after eating. By contrast, in people who were overweight or had obesity, LCN2 levels decreased after a meal.

Based on this post-meal response, the researchers grouped people as non-responders or responders. Non-responders, who showed no increase in LCN2 after a meal, tended to have a larger waist circumference and higher markers of metabolic disease, including BMI, body fat, increased blood pressure, and increased blood glucose. However, people who had lost weight after gastric bypass surgery were found to have a restored sensitivity to LCN2, changing their status from non-responders before their surgery, to responders afterwards.

Taken together, these results mirror those seen in mice, and suggest that this loss of post-meal LCN2 regulation is a new mechanism contributing to obesity and could be a potential target for weight-loss treatments.

After verifying that LCN2 can cross into the brain, the team explored whether treatment with the hormone might reduce food intake and prevent weight gain. To do this, they treated monkeys with LCN2 for a week. They saw a 28% decrease in food intake compared with that before treatment within a week, and the monkeys also ate 21% less than their counterparts who were treated only with saline. Moreover, after only one week of treatment, measurements of body weight, body fat, and blood fat levels showed a declining trend in treated animals.

“We have shown that LCN2 crosses to the brain, makes its way to the hypothalamus, and suppresses food intake in non-human primates,” concludes senior author Stavroula Kousteni, PhD, professor of physiology and cellular biophysics at Columbia University Irving Medical Center. “Our results show that the hormone can curb appetite with negligible toxicity and lay the groundwork for the next level of LCN2 testing for clinical use.”

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