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 6

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

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LIF induces a persistent decrease in body weight, adipose mass, and food...
(A–E) Chow-fed Lepob/J, ob/ob, mice (11-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 48 days (treatment) and subsequently followed for another 29 days (posttreatment) without injections. Body weight (A), food intake (D and E), and ECHO MRI measurements of fat mass (B) and lean mass (C) were measured at the indicated time points for 77 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 39.5, 39.5, and 39.3 g for the PBS-, rLIF-, and rLIF K159A–treated mice, respectively. The average values for fat mass (B) at day 0 were 20.1, 20.6, and 20.9 g for the PBS-, rLIF-, and rLIF K159A–treated mice, respectively. The average values for lean mass (C) at day 0 were 16.7, 15.8, and 16.5 g for the PBS-, rLIF-, and rLIF K159A–treated mice, respectively. (F) Chow-fed Lepob/J, ob/ob, mice (10-week-old males) were housed 3 mice per cage and treated with PBS or rLIF as above for the indicated time interval, and food intake was measured. Every 3 days, 3 mice from each cohort were sacrificed, followed by harvesting and processing of the hypothalamus as described in the Methods. Aliquots (30 μg/lane) of pooled hypothalamic cell lysate from 3 mice treated identically were subjected to IB analysis with the indicated antibodies as described in Methods. The unfilled circles represent the average food intake from the day the 3 mice from each cohort were sacrificed for hypothalamic processing. (A–F) Each value represents mean ± SEM (A–C) or dot plots with mean ± SEM (D–F) of 3 mice (F) or 4 mice (A–E). These results were confirmed in 2 (F) or 3 independent experiments (A–E). *P < 0.05, **P < 0.01, and ***P < 0.001 based on Student’s t test comparing rLIF-treated mice with PBS- or rLIF K159A–treated mice over the respective time interval (D–F) or P value based on use of Generalized Estimating Equation approach with rLIF-treated mice as the reference value (A–C).