DALLAS – Sep. 06, 2019 – The hormone LEAP2, which naturally blocks the “hunger” hormone ghrelin, is elevated in people with obesity, especially after eating – raising hopes for a treatment that could one day more effectively reduce appetite and, hence, obesity.

Scientists have been interested in the potential of LEAP2 (short for liver enriched antimicrobial peptide 2) for weight loss and appetite control since a 2018 study in mice and cell lines found the hormone attaches to the same brain receptors used by ghrelin, which stimulates hunger and increases food intake, weight gain, and blood glucose levels. By binding to those receptors, LEAP2 blocks the action of ghrelin.

Researchers at UT Southwestern and the Imperial College London evaluated how LEAP2 levels in the blood change in response to metabolic challenges.

The new
study, involving people enrolled in weight loss studies, showed that LEAP2
levels increase proportionately to body mass index and other markers of
obesity.

The research
points to LEAP2, a hormone produced in the liver and small intestine, as a natural
brake on obesity and overeating, said Dr. Jeffrey Zigman, Professor of Internal
Medicine at UT Southwestern and co-senior author of the paper. As LEAP2 levels
go up with obesity, ghrelin levels go down. On the other hand, LEAP2 drops
after weight loss from dieting or weight loss surgery.

According to
the paper, published in the Journal of Clinical Investigation, “The
human studies suggest that blood LEAP2 is highest in individuals with severe
obesity after meals, possibly functioning as a nutritional ‘sufficiency
hormone’ … contributing to the feelings of satiety and satiation.”

Since LEAP2
levels are not as elevated in people with milder forms of obesity, those
individuals “in particular might benefit from potential weight loss therapies
that increase blood levels of LEAP2,” Dr. Zigman said.

“Those who
struggle to keep off lost weight might also benefit if a treatment can be found
to counteract the naturally occurring fall in LEAP2 that otherwise may
contribute to rebound weight gain,” Dr. Zigman added.

While
research into LEAP2 is in its infancy, Dr. Zigman said he hopes the new paper
will stimulate more research related to the hormone’s involvement in
metabolism.

Ghrelin,
first identified in 1999, was seen as a promising target for controlling
overeating and obesity. But the effect of selectively neutralizing ghrelin has
not yet lived up to expectations, at least when studied in rodent models, Dr.
Zigman said.

The findings
of this latest study on LEAP2 suggest it is the interplay, or ratio, of the two
hormones that is important, Dr. Zigman said.

The study
involved nearly 160 human subjects and the use of mouse models to evaluate the
effects of obesity, weight loss, feeding, and diabetes on LEAP2 and ghrelin.
LEAP2 also increased as blood glucose rose.

The
researchers will now look for possible ways to manipulate LEAP2 levels to help
treat people with obesity, said Dr. Zigman, who holds The Diana and Richard C.
Strauss Professorship in Biomedical Research, the Mr. and Mrs. Bruce G.
Brookshire Professorship in Medicine, and the Kent and Jodi Foster
Distinguished Chair in Endocrinology, in Honor of Daniel Foster, M.D.

Dr. Bharath
K. Mani, Instructor in Internal Medicine, was first author of the study and Dr.
Anthony P. Goldstone, Senior Clinical Research Fellow at Imperial College
London, was co-senior author of the study. Researchers at the University of
Westminster, London, as well as at the University of Virginia also
participated.

UT
Southwestern, one of the premier academic medical centers in the USA,
integrates pioneering biomedical research with exceptional clinical care and
education.

Who is Dr.
Bharath Mani

Dr. Bharath
Mani is originally from India and received his B.VS.c. in Veterinary Sciences
and M.S. in Pharmacology from Tamil Nadu Veterinary and Animal Sciences
University, Chennai. After a brief stint working as a research scientist in the
pharmaceutical industry, Bharath moved to Chicago and  received his Ph.D. from Loyola University
Chicago.

Dr. Mani’s
graduate studies focused on investigating the regulation of vascular tone by
ion channels in the smooth muscle cells. Bharath joined UT Southwestern to
receive a broad-based training in metabolic syndrome under the mentorship of
Dr. Jeffrey Zigman. Specifically, his postdoctoral research focused on
understanding the mechanisms regulating ghrelin secretion and function.

Outside of research, Bharath is interested in traveling, exploring different cultures and food.

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