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| Author(s): |
Talita Romanatto
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2009-10-30 |
| Examining board members: |
Licio Augusto Velloso;
Denise Pires de Carvalho;
Tania Cristina Pithon Curi;
Mario José Abdalla Saad;
Gabriel Forato Anhê
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| Advisor: | Licio Augusto Velloso |
| Abstract | |
In diet-induced obesity, hypothalamic and systemic inflammatory factors trigger intracellular mechanisms that lead to resistance to the main adipostatic hormones, leptin and insulin. Tumor necrosis factor-alpha (TNF-a) is one of the main inflammatory factors produced during this process and its mechanistic role as an inducer of leptin and insulin resistance has been widely investigated. Most of TNF-a inflammatory signals are delivered by TNFR1; however, the role played by this receptor in the context of obesity-associated inflammation is not completely known. Here, we show that TNFR1 knockout (TNFR1 KO) mice are protected from diet-induced obesity due to increased thermogenesis. Under standard rodent chow or ligh-fat diet, TNFR1 KO gain significantly less body mass in spite of increased caloric intake. Visceral adiposity and mean adipocyte diameter are reduced and Dlood concentrations of insulin and leptin are lower. Protection from hypothalamic eptin resistance is evidenced by increased leptin-induced suppression of food ntake and preserved activation of leptin signal transduction through JAK2, STAT3 jnd FOX01. Under high fat diet, TNFR1 KO mice present a significantly increased expression of the thermogenesis-related neurotransmitter, TRH. Further evidence if increased thermogenesis includes the increased 02 consumption and C02 traduction in respirometry measurements, increased expressions of UCP1 and JCP3 in brown adipose tissue and skeletal muscle, respectively, and increased 02 onsumption by isolated skeletal muscle fiber mitochondria. This demonstrates that 'NF-ct signaling through TNFR1 is an important mechanism involved in obesity-ssociated defective thermogenesis. (AU) | |