Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration.

BACKGROUND: Obesity is associated with increased recurrence and reduced survival of breast cancer. Adipocytes constitute a significant component of breast tissue, yet their role in provisioning metabolic substrates to support breast cancer progression is poorly understood. RESULTS: Here, we show that co-culture of breast cancer cells with adipocytes revealed cancer cell-stimulated depletion of adipocyte triacylglycerol. Adipocyte-derived free fatty acids were transferred to breast cancer cells, driving fatty acid metabolism via increased CPT1A and electron transport chain complex protein levels, resulting in increased proliferation and migration. Notably, fatty acid transfer to breast cancer cells was enhanced from "obese" adipocytes, concomitant with increased stimulation of cancer cell proliferation and migration. This adipocyte-stimulated breast cancer cell proliferation was dependent on lipolytic processes since HSL/ATGL knockdown attenuated cancer cell responses. CONCLUSIONS: These findings highlight a novel and potentially important role for adipocyte lipolysis in the provision of metabolic substrates to breast cancer cells, thereby supporting cancer progression

Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration.

BACKGROUND: Obesity is associated with increased recurrence and reduced survival of breast cancer. Adipocytes constitute a significant component of breast tissue, yet their role in provisioning metabolic substrates to support breast cancer progression is poorly understood. RESULTS: Here, we show that co-culture of breast cancer cells with adipocytes revealed cancer cell-stimulated depletion of adipocyte triacylglycerol. Adipocyte-derived free fatty acids were transferred to breast cancer cells, driving fatty acid metabolism via increased CPT1A and electron transport chain complex protein levels, resulting in increased proliferation and migration. Notably, fatty acid transfer to breast cancer cells was enhanced from "obese" adipocytes, concomitant with increased stimulation of cancer cell proliferation and migration. This adipocyte-stimulated breast cancer cell proliferation was dependent on lipolytic processes since HSL/ATGL knockdown attenuated cancer cell responses. CONCLUSIONS: These findings highlight a novel and potentially important role for adipocyte lipolysis in the provision of metabolic substrates to breast cancer cells, thereby supporting cancer progression

Correction: Insulin and diet-induced changes in the ubiquitin-modified proteome of rat liver

<p>Correction: Insulin and diet-induced changes in the ubiquitin-modified proteome of rat liver</p

Insulin and diet-induced changes in the ubiquitin-modified proteome of rat liver

<div><p>Ubiquitin is a crucial post-translational modification regulating numerous cellular processes, but its role in metabolic disease is not well characterized. In this study, we identified the <i>in vivo</i> ubiquitin-modified proteome in rat liver and determined changes in this ubiquitome under acute insulin stimulation and high-fat and sucrose diet-induced insulin resistance. We identified 1267 ubiquitinated proteins in rat liver across diet and insulin-stimulated conditions, with 882 proteins common to all conditions. KEGG pathway analysis of these proteins identified enrichment of metabolic pathways, TCA cycle, glycolysis/gluconeogenesis, fatty acid metabolism, and carbon metabolism, with similar pathways altered by diet and insulin resistance. Thus, the rat liver ubiquitome is sensitive to diet and insulin stimulation and this is perturbed in insulin resistance.</p></div

Rat liver ubiquitome.

<p><b>(A)</b> Experimental design of the ubiquitomic analysis rat liver. <b>(B)</b> Immunoblot analysis of protein ubiquitination in representative samples of rat liver lysates. (<b>C)</b> Venn diagram of previously identified protein in this study and that in the known rat ubiquitome. <b>(D)</b> Ontology analysis of identified ubiquitinylated proteins. <b>(E)</b> Gluconeogenesis/Glycolysis biochemical pathway with ubiquitinylated enzymes marked in red.</p

High-fat, high-sucrose diet alters the ubiquitome of the rat liver.

<p><b>(A)</b> Venn diagram of identified proteins ubiquitinated in HFSD compared to HFSD + Insulin. <b>(B)</b> Ontology analysis of identified ubiquitinylated proteins in HFSD compared to HFSD + Insulin. <b>(C)</b> STRING analysis of differentially ubiquitinated proteins. <b>(D)</b>. Ontology analysis of identified ubiquitinated proteins responsive to insulin in Chow but not in HFSD.</p

High-fat, high-sucrose feeding results in obesity and insulin resistance in male rats.

<p><b>(A)</b> Body mass, <b>(B)</b> epidydimal fat pad mass, and <b>(C)</b> liver triacylglycerol content of rats fed a high fat diet for 4 weeks or chow control. * <i>P</i> < 0.05 vs Chow for each condition by Two-Way ANOVA followed by Tukey’s Multiple Comparisons test. <b>(D)</b> Plasma insulin and <b>(E)</b> blood glucose levels in rats infused with insulin for 10 mins at 0.5 U/kg/h. <b>(F)</b> Liver Akt phosphorylation. * <i>P</i> < 0.05 vs Basal for each condition, # <i>P</i> < 0.05 vs Chow Insulin by Two-Way ANOVA followed by Tukey’s Multiple Comparisons test. Data are mean ± SEM, n = 4.</p