Modulation of hypothalamic AMPK and JNK1 by Olanzapine controls energy balance and hepatic lipogenesis: additional benefits of PTP1B inhibition

  1. Da Silva Ferreira, Vítor Manuel
Dirixida por:
  1. Angela María Martínez Valverde Director
  2. Patricia P. Rada Llano Director

Universidade de defensa: Universidad Autónoma de Madrid

Fecha de defensa: 06 de outubro de 2023

Tribunal:
  1. Manuel Ros Pérez Presidente/a
  2. Cintia Folgueira Cobos Secretaria
  3. Ophelia Le Thuc Vogal
  4. Carlos Guillén Viejo Vogal
  5. Miguel Antonio López Pérez Vogal

Tipo: Tese

Resumo

Schizophrenia is a chronic psychiatric disorder which is treated with second generation antipsychotics (SGAs). However, many patients on treatment develop metabolic dysfunctions such as a body weight gain, hyperglycemia, dyslipidemia and hepatic steatosis. Among target candidates to combat metabolic diseases, protein tyrosine phosphatase-1B (PTP1B), a critical negative modulator of leptin and insulin signaling, is currently considered as a therapeutic target for obesity and type 2 diabetes. In this Thesis we have evaluated the effects of olanzapine (OLA), a widely prescribed, but highly obesogenic SGA, in male mice analyzing changes in body weight and energy balance modulated by the hypothalamus-brown/beige adipose tissue axis. We also investigated OLA effects in hepatic lipid metabolism focusing on the hypothalamus-liver interactome. Further, we explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin and insulin hypersensitivity protected against obesity and metabolic syndrome. Studies were conducted in male mice receiving OLA orally (supplemented in the diet) or injected via intraperitoneal (i.p.). Preliminary studies were conducted in females receiving OLA via i.p. Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but only WT mice gained weight. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake. In i.p. treated-mice, reduced hypothalamic AMP-dependent protein kinase (AMPK) phosphorylation concurred with elevations in Uncoupling Protein-1 (UCP-1) in brown adipose tissue (BAT) and subcutaneous white adipose tissue (iWAT) and increased energy expenditure. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutively AMPK activation in the hypothalamus. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels in the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain. Additionally, we found that OLA i.p. treatment induced mild oxidative stress and inflammation in the hypothalamus in a Jun N-terminal kinase-1 (JNK1)-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve, an effect concurrent with a starvation-like molecular signature, thereby preventing steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against weight gain and hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation upon i.p. administration, strongly suggests that targeting PTP1B might be a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner