Cachexia-associated adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin
Gurpreet K. Arora, Arun Gupta, Sriram Narayanan, Tong Guo, Puneeth Iyengar, Rodney E. Infante
Gurpreet K. Arora, Arun Gupta, Sriram Narayanan, Tong Guo, Puneeth Iyengar, Rodney E. Infante
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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 8

LIF induces a persistent decrease in body weight, adipose mass, and food intake in db/db mice.

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LIF induces a persistent decrease in body weight, adipose mass, and food...
(A–D) Chow-fed Leprdb/J, db/db, mice (8-week-old males) were housed 4 mice per cage and injected i.p. with 100 μl PBS in the absence or presence of rLIF or rLIF K159A at 80 μg/kg body weight twice daily for 47 days (treatment) and subsequently followed for another 31 days (posttreatment) without injections. Body weight (A), food intake (B), and ECHO MRI measurements of fat mass (C) and lean mass (D) were measured at 9 a.m. at the indicated time points for 78 days. Body weight, fat mass, and lean mass are shown relative to the average day 0 reference value for each respective cohort. The average values for body weight (A) at day 0 were 35.8, 34.8, and 34.3 g for the PBS-, rLIF-, and rLIF K159A–treated mice, respectively. The average values for fat mass (C) at day 0 were 16.8, 16.7, and 16.9 g for the PBS-, rLIF-, and rLIF K159A–treated mice, respectively. The average values for lean mass (D) at day 0 were 16.1, 15.3, and 15.1 g for the PBS-, rLIF-, and rLIF K159A–treated mice, respectively. Each value represents mean ± SEM of 4 mice. These results were confirmed in 2 independent experiments. ***P < 0.001 based on Student’s t test (B) or P value based on use of Generalized Estimating Equation approach comparing multiple groups over time with rLIF-treated mice as the reference value (A, C, D).