Anti-tumor drug promotes weight loss in mice
Mouse study could indicate potential for stimulating a natural hunger- suppressing pathway
Date:
February 24, 2022
Source:
PLOS
Summary:
An anti-tumor drug promotes weight loss in mice at low doses by
activating a natural hunger-suppressing pathway, according to a new
study. The results provide a promising new avenue for development
of anti-obesity treatments.
FULL STORY ==========================================================================
An anti-tumor drug promotes weight loss in mice at low doses by activating
a natural hunger-suppressing pathway, according to a new study publishing
Feb. 24 in the open-access journal PLOS Biology by Jiang Wei Wu and
colleagues at Northwest A&F University in Shaanxi, China. The results
provide a promising new avenue for development of anti-obesity treatments.
========================================================================== Growth differentiation factor 15 (GDF15) is a hormone that circulates
in response to a wide variety of stimuli, including stress. Previous
work has shown that elevation of GDF15 leads to a drop in body weight,
while suppression of it leads to obesity.
To search for drugs that could increase GDF15 production, the authors
turned to the "Connectivity Map," a database of gene expression profiles
of human cells in response to drug exposure. They found that cells
exposed to a drug called camptothecin increased their expression of
GDF15. Camptothecin is derived from the Asian tree Camptotheca acuminata,
and is a known inhibitor of a DNA repair enzyme (hence its use as an
anti-tumor drug).
In obese mice, the authors showed that oral administration of camptothecin rapidly elevated the level of GDF15 in the blood, and over the course
of 30 days, reduced food intake by about 12% and body weight by about
11%. In contrast, in lean mice, camptothecin did not elevate GDF15 and
there was no effect on either food intake or body weight.
Camptothecin's effect was specific to GDF15, and GDF15 exerted its
effect through its receptor, called GFRAL, the team showed, since an
antibody against GDF15 prevented the weight loss, as did knocking down
GFRAL expression.
Camptothecin has been studied in anti-cancer trials, but was ultimately
set aside due to safety concerns. Its safety as an anti-obesity drug
has yet to be determined, Wu said, but noted that the dose used in this
study, if scaled up to a human, would be about one-thirtieth of the lowest
dose used in human anti- cancer trials. Additionally, the anti-obesity mechanism appears to be separate from the anti-cancer mechanism, which
involves blocking the function of the DNA-repair enzyme topoisomerase,
and to function at a much lower drug concentration.
"We believe our results convincingly argue that camptothecin may have therapeutic benefits for obesity and its associated metabolic disorders,"
Wu says. "Further study is needed to evaluate its efficacy and safety
in advanced models to increase the translational impact." Wu adds, "In
this study, by using in silico drug-screening approach, we discovered
that Camptothecin (CPT), a previously identified anti-tumor drug by
the US National Cancer Institute, is a GDF15 inducer. CPT elevates
circulating GDF15 via activation of hepatic ISR pathway, this activates
the GDF15 receptor GFRAL in the hindbrain AP, which subsequently
suppresses food intake and reduces body weight in obese mice." ========================================================================== Story Source: Materials provided by PLOS. Note: Content may be edited
for style and length.
========================================================================== Journal Reference:
1. Jun Feng Lu, Meng Qing Zhu, Bao Cai Xie, Xiao Chen Shi, Huan Liu,
Rui Xin
Zhang, Bo Xia, Jiang Wei Wu. Camptothecin effectively treats
obesity in mice through GDF15 induction. PLOS Biology, 2022; 20
(2): e3001517 DOI: 10.1371/journal.pbio.3001517 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/02/220224140853.htm
--- up 11 weeks, 5 days, 7 hours, 13 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)