TLR4 as crossroad of inflammation and energy metabolism: Role of adipose tissue in cancer cachexia

• Grant number: 18/20905-1
• Support Opportunities: Scholarships abroad - Research
• Start date: June 30, 2019
• End date: July 29, 2020
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Miguel Luiz Batista Junior
• Grantee: Miguel Luiz Batista Junior
• Host Investigator: Stephen Robert Farmer
• Host Institution: Pró-Reitoria Acadêmica. Universidade de Mogi das Cruzes (UMC). Campus da Sede Mogi das Cruzes. Mogi das Cruzes , SP, Brazil
• Institution abroad: Boston University (BU), United States

Abstract

Cachexia is characterized as a syndrome that affects multiple compartments and systems of the tumor-bearing organism, breaking the natural state of balance between the systems, leading to metabolic "chaos." It is highly prevalent in cancer patients, especially in patients with gastrointestinal cancer (> 60%) and in more than 25% of patients; it is the leading cause of death. Recently, several independent studies have demonstrated that white adipose tissue (WAT), in addition to being described as an organ with important endocrine function, may act as a secretory or target organ of inflammatory molecules during the development of cachexia syndrome. In this way, it seems helpful to investigate the effects of cachexia per se. The current views of the syndrome either as an inflammatory process or as a physiological imbalance so profound as to be proposed as a causative agent and not a consequence of the appearance of tumors demonstrate the insufficiency of the information obtained until the present moment.Acute fat mass reduction is one of the leading clinical "markers" of cancer cachexia. This process seems to be the result of several metabolic and inflammatory changes, due to factors produced by the host itself and by the tumor itself. Thus, having the inflammatory model as a hypothesis to be tested, our group recently demonstrated the relevance of subcutaneous adipose tissue as a vital source of inflammatory mediators, especially IL-6 and adiponectin. These adipokines also presented a cachectic biomarker function (clinical evolution), since these adipokines correlated with the magnitude of reduction of body weight. Also, our recent studies have shown that, in cancer-associated cachexia, morpho-functional changes in WAT are characterized by phenotypic changes in white adipocytes to a profile closer to brown adipocytes. This process, described as browning of WAT, seems to be related to the dysfunction in the energetic metabolism of this tissue.On the other hand, the vast majority of studies are rOn the other hand, most studies are restricted to evaluating morphological changes, neglecting tissue inflammation and, mainly, events that result in alterations in energy metabolism, tissue catabolism and later in systemic inflammation. Because of the role that Toll 4 receptors (TLR4) play in controlling lipolysis, inflammation and consequent remodeling of adipose tissue, we postulate that the activation of these receptors plays an essential role in the reduction of fat mass in cachexia. In this regard, initial data suggest that TLR4 antagonist treatment attenuates TAB remodeling and increases survival of cachexia-carrying mice. Also, despite the critical role of innate immunity receptors as a crossroad between inflammatory and metabolic events, as far as we know, few or no studies have evaluated such relationships and their role in changes in body energy metabolism during cachexia. Thus, we propose to study the effect of cachexia on adipose tissue remodeling, especially the repercussions on body energy metabolism and the possible role of TLR4 as a crossroad between inflammation and energetic metabolism in beige adipocytes.

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SANTOS, GABRYELLA S. P.; COSTA, ALINNE C.; PICOLI, CAROLINE C.; ROCHA, BEATRIZ G. S.; SULAIMAN, SHEU O.; RADICCHI, DEBORA C.; PINTO, MAURO C. X.; BATISTA, JR., MIGUEL L.; AMORIM, JAIME H.; AZEVEDO, VASCO A. C.; et al. ympathetic nerve-adipocyte interactions in response to acute stres. JOURNAL OF MOLECULAR MEDICINE-JMM, v. 100, n. 2, NOV 2021. (18/20905-1)

BIAGI JR, CARLOS ALBERTO OLIVEIRA; CURY, SARAH SANTILONI; ALVES, CLEIDSON PADUA; RABHI, NABIL; SILVA JR, WILSON ARAUJO; FARMER, STEPHEN R.; CARVALHO, ROBSON FRANCISCO; BATISTA JR, MIGUEL LUIZ. Multidimensional Single-Nuclei RNA-Seq Reconstruction of Adipose Tissue Reveals Adipocyte Plasticity Underlying Thermogenic Response. CELLS, v. 10, n. 11, NOV 2021. (18/20905-1)

PICOLI, CAROLINE DE CARVALHO; GILIO, GUSTAVO RENAN; HENRIQUES, FELIPE; LEAL, LUANA GARCIA; BESSON, JEAN CARLOS; LOPES, MAGNO ALVES; FRANZOI DE MORAES, SOLANGE MARTA; HERNANDES, LUZMARINA; BATISTA JUNIOR, MIGUEL LUIZ; PERES, SIDNEY BARNABE. Resistance exercise training induces subcutaneous and visceral adipose tissue browning in Swiss mice. Journal of Applied Physiology, v. 129, n. 1, p. 66-74, JUL 2020. (18/20905-1, 15/19259-0)

LEAL, LUANA G.; LOPES, MAGNO A.; PERES, SIDNEY B.; BATISTA, JR., MIGUEL L.. Exercise Training as Therapeutic Approach in Cancer Cachexia: A Review of Potential Anti-inflammatory Effect on Muscle Wasting. FRONTIERS IN PHYSIOLOGY, v. 11, FEB 4 2021. (18/20905-1, 15/19259-0)

BATISTA, MIGUEL L., JR.; MESHULAM, TOVA; DESEVIN, KATHLEEN; RABHI, NABIL; FARMER, STEPHEN R.. Three-Dimensional Adipocyte Culture as a Model to Study Cachexia-Induced White Adipose Tissue Remodeling. JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, v. N/A, n. 167, p. 9-pg., 2021-01-01. (18/20905-1)

BATISTA, JR., MIGUEL L.; MESHULAM, TOVA; DESEVIN, KATHLEEN; RABHI, NABIL; FARMER, STEPHEN R.. Three-Dimensional Adipocyte Culture as a Model to Study Cachexia-Induced White Adipose Tissue Remodeling. JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, n. 167, JAN 2021. (18/20905-1)