Characterization of hypothalamic AMPK/mTOR in cancer-induced anorexia

Author(s)

Gustavo Duarte Pimentel

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2015-01-30

Examining board members

José Barreto Campello Carvalheira; Jose Antonio Rocha Gontijo; Gabriel Forato Anhê; Lila Missae Oyama; Franco Battista Ennio Folli

• Advisor: José Barreto Campello Carvalheira

Abstract

The theory of diseases generated by inflammatory cytokine brought over the years evidence that the organism may produce cytokine with beneficial and deleterious responses. Nowadays, it is clear that the inflammation is a key mechanism in cancer pathophysiology. Interestingly, several studies suggest that hypothalamic AMPK and mTOR, important molecules in the energy balance control also is responsible for modulation of both inflammation and anorexia. The studies presented herein observed that: 1) Inhibition of hypothalamic AMPK leads to weight loss and central and systemic inflammation which potentiates the tumor growth. However, AMPK activation with AICAR, salicylate and vector viral might reverse the cancer-mediated anorexia. Nevertheless, benefic effects of AICAR are blunted with a combination of cholinergic antagonists, suggesting that ventromedial of hypothalamus (VMH)-specific AMPK action is responsible for the anorexia and inflammation control. 2) VMH-specific AMPK, particularly the isoform alpha 1 activates thermogenesis increasing heat production which switches the white adipose tissue in beige. Furthermore, ?3 adrenergic antagonist and AMPK activation were able to attenuate the heal generation, block the "browning of WAT" and improve the cancer cachexia. 3) Cancer rats have activated IKK/mTOR pathway in arcuate nucleus (ARC) of the hypothalamus. In contrast, neutralization of S6K through adenovirus was able to improve anorexia. Therefore, our data show evidences that the hypothalamus a key center that integrates a number of mechanisms triggered by cancer-induced anorexia and -cachexia, opening new horizons for the treatment of cancer (AU)

• FAPESP's process: 11/02806-7 - Characterization of the hypothalamic AMPK/mTOR in cancer-induced anorexia
• Grantee: Gustavo Duarte Pimentel
• Support Opportunities: Scholarships in Brazil - Doctorate