Cachexia-associated adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin
Gurpreet K. Arora, … , Puneeth Iyengar, Rodney E. Infante
Gurpreet K. Arora, … , Puneeth Iyengar, Rodney E. Infante
Published July 26, 2018
Citation Information: JCI Insight. 2018;3(14):e121221. https://doi.org/10.1172/jci.insight.121221.
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Research Article Metabolism Oncology

Cachexia-associated adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin

Abstract

Cachexia syndrome consists of adipose and muscle loss, often despite normal food intake. We hypothesized that cachexia-associated adipose wasting is driven in part by tumor humoral factors that induce adipocyte lipolysis. We developed an assay to purify secreted factors from a cachexia-inducing colon cancer line that increases lipolysis in adipocytes and identified leukemia inhibitory factor (LIF) by mass spectrometry. Recombinant LIF induced lipolysis in vitro. Peripheral LIF administered to mice caused >50% loss of adipose tissue and >10% reduction in body weight despite only transient hypophagia due to decreasing leptin. LIF-injected mice lacking leptin (ob/ob) resulted in persistent hypophagia and loss of adipose tissue and body weight. LIF’s peripheral role of initiating lipolysis in adipose loss was confirmed in pair-fed ob/ob mouse studies. Our studies demonstrate that (a) LIF is a tumor-secreted factor that promotes cachexia-like adipose loss when administered peripherally, (b) LIF directly induces adipocyte lipolysis, (c) LIF has the ability to sustain adipose and body weight loss through an equal combination of peripheral and central contributions, and (d) LIF’s central effect is counterbalanced by decreased leptin signaling, providing insight into cachexia’s wasting, despite normophagia.

Authors

Gurpreet K. Arora, Arun Gupta, Sriram Narayanan, Tong Guo, Puneeth Iyengar, Rodney E. Infante

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Figure 5

LIF’s central effect persists with coadministration of leptin.

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LIF’s central effect persists with coadministration of leptin. (A–C) Com...
(A–C) Combination treatment of C57BL/6J mice with rLIF and leptin. On day –15, chow-fed C57BL/6J mice (11-week-old males) were injected i.p. with 100 μl PBS containing 80 μg/kg body weight rLIF twice daily for 15 days with average fat mass loss of ~30%–40% and weight loss of ~10%. On day 0, mice were randomized and housed 4 mice per cage and treated with 100 μl PBS in the absence or presence of 80 μg/kg body weight rLIF twice daily and/or 5 mg/kg leptin once daily for 9 days. ECHO MRI measurements of fat mass (B), body weight (C), and food intake (A) were measured at the indicated time points and are shown relative to the average day 0 reference value for each respective cohort. The average day 0 values for fat mass were 1.7, 1.7, 1.6, and 1.7 g and body weight were 22.1, 23.5, 21.5, and 23.1 g for the PBS, rLIF, rleptin, and rLIF plus rleptin cohorts, respectively. Each value represents dot plot with mean ± SEM (A) or mean ± SEM (B–C) of 4 mice. (A–C) These results were confirmed in 2 independent experiments. *P < 0.05 and ***P < 0.001 based on Student’s t test (C) or P value based on use of Generalized Estimating Equation approach comparing multiple groups over time with rLIF + rleptin–treated mice as the reference value (A and B).