Brown fat does not cause cachexia in cancer patients: A large retrospective longitudinal FDG-PET/CT cohort study

Abstract

Background Brown adipose tissue (BAT) is a specialized form of adipose tissue, able to increase energy expenditure by heat generation in response to various stimuli. Recently, its pathological activation has been implicated in the pathogenesis of cancer cachexia. To establish a causal relationship, we retrospectively investigated the longitudinal changes in BAT and cancer in a large FDG-PET/CT cohort. Methods We retrospectively analyzed 13 461 FDG-PET/CT examinations of n = 8 409 patients at our institution from the winter months of 2007-2015. We graded the activation strength of BAT based on the anatomical location of the most caudally activated BAT depot into three tiers, and the stage of the cancer into five general grades. We validated the cancer grading by an interreader analysis and correlation with histopathological stage. Ambient temperature data (seven-day average before the examination) was obtained from a meteorological station close to the hospital. Changes of BAT, cancer, body mass index (BMI) and temperature between the different examinations were examined with Spearman's test and a mixed linear model for correlation, and with a causal inference algorithm for causality. Results We found n = 283 patients with at least two examinations and active BAT in at least one of them. There was no significant interaction between the changes in BAT activation, cancer burden or BMI. Temperature changes exhibited a strong negative correlation with BAT activity (% =-0.57, p<0.00001). These results were confirmed with the mixed linear model. Causal

Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer

“…Data from other mouse models and human studies of CACS show that WAT lipolysis is an essential feature of CACS 17,67,68 , however, the role of browning is more controversial. In certain models, browning exacerbates the negative energy state 7,31 , but this finding is not consistent with clinical studies in subjects with lung cancer nor our data from the KL mice [69][70][71][72][73][74][75] . We speculate that the browning observed in KL mice with CACS occurs in response to a reduction in core temperature mediated by BAT dysfunction.…”

Blocking ActRIIB signaling and restoring appetite reverses cachexia and improves survival in mice with lung cancer

“…In certain models, browning exacerbates the negative energy state 9,41 , but this finding is not consistent with clinical studies in subjects with lung cancer nor our data from the KL mice [42][43][44][45][46][47][48][49] . We speculate that the browning observed in KL mice with CACS occurs in response to an increased demand for thermogenesis following the loss of the abdominal "insulation" provided by skeletal muscle and adipose tissues.…”

Metabolic Reprogramming in Adipose Tissue During Cancer Cachexia

“…A direct correlation between BAT volume and mortality was described in a large group of cancer patients ( 55 ). However, two recent studies failed to demonstrate a link between BAT activation and weight loss ( 56 , 57 ). Factors influencing detection of BAT activity using FDG-PET/CT scan were described in a large retrospective study ( 58 ).…”