Indiana University-Purdue University Indianapolis (IUPUI) / Cachexia, the involuntary loss of fat and muscle is associated with pancreatic ductal adenocarcinoma (PDAC), contributing to its 90% 5-year mortality rate. Elevated Interleukin-6 (IL-6) expression is associated with cachexia severity and reduced survival in patients. IL-6 in cancer is well documented, but IL-6 signaling crosstalk among tissues is not. IL-6 signals by binding membrane-bound IL-6 receptor (IL-6R) (classical signaling) or soluble IL- 6R (sIL6R; trans-signaling) produced by shedding of the membrane receptor primarily from muscle, liver and leukocytes. Herein I investigate the role of tumorderived IL-6 on muscle and fat crosstalk in PDAC. Loss of IL-6 expression in murine KPC PDAC cells was accomplished by CRISPR/Cas9 mutagenesis of the Il6 gene. Orthotopic KPC IL-6 knockout (KPC-IL-6KO) tumor-bearing mice had reduced cachexia, with attenuated fat loss and no significant muscle loss, and longer survival versus KPC controls. Only KPC tumor-bearing mice had significant myosteatosis, aberrant branched chain amino acid and fatty acid metabolism, and reduced pyruvate entry into the TCA-cycle, determined by increased pyruvate dehydrogenase kinase 4 (PDK4) expression in muscle. Muscle was a main source of sIL6R, and fat a primary contributor of IL-6 in KPC tumor-bearing mice. Myosteatosis leads to activation of lipid-sensitive kinases like protein kinase C theta (PKCθ, gene name Prkcq) in muscle. KPC tumorbearing mice had increased muscle PKCθ activation, and PKCθ is known to regulate metabolism and inflammation. Prkcq-/- KPC tumor-bearing mice had reduced cachexia and maintained muscle mass and force production versus wild type tumor-bearing mice. Together these data implicate progressive signaling mechanisms whereby tumor-derived IL-6 is associated with increased muscle IL6R expression and fat lipolysis, promoting myosteatosis and muscle PKCθ activation, ultimately increasing cachexia severity in PDAC. / 2021-11-03

Submitted by FERNANDA DA SILVA VON PORSTER (fdsvporster@univates.br) on 2016-02-02T16:47:09Z No. of bitstreams: 3 license_text: 22064 bytes, checksum: ef48816a10f2d45f2e2fee2f478e2faf (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) 2013RafaelaMundstockdeAzevedoBastian.pdf: 749375 bytes, checksum: b76d59045d784f0c33faadd0accae511 (MD5) / Approved for entry into archive by Ana Paula Lisboa Monteiro (monteiro@univates.br) on 2016-02-03T16:52:14Z (GMT) No. of bitstreams: 3 license_text: 22064 bytes, checksum: ef48816a10f2d45f2e2fee2f478e2faf (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) 2013RafaelaMundstockdeAzevedoBastian.pdf: 749375 bytes, checksum: b76d59045d784f0c33faadd0accae511 (MD5) / Made available in DSpace on 2016-02-03T16:52:14Z (GMT). No. of bitstreams: 3 license_text: 22064 bytes, checksum: ef48816a10f2d45f2e2fee2f478e2faf (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) 2013RafaelaMundstockdeAzevedoBastian.pdf: 749375 bytes, checksum: b76d59045d784f0c33faadd0accae511 (MD5) / A obesidade é uma doença crônica de origem multifatorial que pode se desenvolver a partir de fatores comportamentais, metabólicos, psicológicos, e genéticos. A nutrigenética estuda os efeitos da variação genética na interação dieta-doença, o que inclui a identificação e caracterização dos genes relacionados ou até mesmo responsáveis pelas diferentes respostas aos nutrientes. Objetivo: Investigar a relação entre a dieta e os polimorfismos rs2228145 do gene IL6R e rs2069845 do gene IL6 sobre marcadores biológicos do metabolismo (parâmetros bioquímicos e antropométricos, através da técnica da PCR-Real Time. Metodologia: A amostra foi composta por indivíduos provenientes do Ambulatório de Nutrição do Universidade do Vale do Taquari Univates. O consumo alimentar foi avaliado através do recordatório 24 horas pelo software Dietwin 2008. A análise da composição corporal foi realizada através da avaliação antropométrica e do exame de bioimpedância. Foram dosados os parâmetros bioquímicos de glicemia, colesterol total, HDL e triglicerídeos, e calculada a fração LDL. As interações dos polimorfismos rs2228145 e rs2069845 entre o consumo de macro e micronutrientes para os desfechos dos parâmetros bioquímicos e antropométricos foram analisadas através do procedimento backward stepwise pelo software SPSS 19.0. Resultados: A amostra foi composta por um total de 344 indivíduos, dos quais 77% eram do gênero feminino e 23% do gênero masculino, com idade média de 25,8 anos (±6,9). Observaram-se associações entre dieta e o polimorfismo rs2228145 do gene IL6R para os desfechos de glicemia, HDL, IMC e circunferência da cintura. Já o polimorfismo rs2069845 do gene IL6 mostrou associação entre dieta para o desfecho de circunferência da cintura. Conclusão: Após a análise do consumo de macro e micronutrientes, dos parâmetros bioquímicos e antropométricos, juntamente com a análise molecular da amostra pode-se observar diversos efeitos e associações entre esses fatores e os polimorfismos. Essas associações dos polimorfismos com a dieta nos remete ao fato de que cada indivíduo é único e pode apresentar respostas dietéticas diferentes de acordo com seu genótipo. / Obesity is a chronic disease of multifactorial origin that can develop from behavioral, metabolic, psychological, and genetic factors. Nutrigenetic study the effects of genetic variation in diet-disease interaction, which includes the identification and characterization of the genes related or even responsible for the different responses to nutrients. Objective: To investigate the relationship between diet and the polymorphisms rs2228145 of the gene IL6R and rs2069845 of the gene IL6 on biochemical and anthropometric parameters, through the technique of Real - Time PCR. Methods: The sample consisted of individuals from the nutrition clinic of the University Center Univates. Dietary intake was assessed by the 24-hour recall by software Dietwin 2008. The body composition analysis was performed using anthropometric and bioimpedance exams. The biochemical parameters measured were blood glucose, total cholesterol, HDL and triglycerides and LDL calculated. The interactions of polymorphisms rs2228145 and rs2069845 between the consumption of macro and micronutrients for the outcomes of anthropometric and biochemical parameters were analyzed by backward stepwise procedure by SPSS 19.0 software. Results: The sample comprised a total of 344 individuals, of whom 77% were female and 23% male, with mean age of 25.8 years (± 6.9). Associations were observed between diet and the polymorphism rs2228145 of IL6R gene for glucose, HDL, BMI and waist circumference outcomes. The polymorphism rs2069845 of the IL6 gene showed an association between diet for the outcome of waist circumference. Conclusion: After analyzing the consumption of macro and micronutrients, biochemical and anthropometric parameters, together with the molecular analysis of the sample different effects and associations between these factors and polymorphisms can be observed. These associations relates to the fact that each individual is unique and may have different dietary responses according to their genotype