Unit:
Department of PharmacyLibrary of the School of Science
Dissertation committee:
Ανδρέας Παπαπετρόπουλος, Καθηγητής, Τμήμα Φαρμακευτικής, Ε.Κ.Π.Α.
Ιωάννα Ανδρεάδου, Καθηγήτρια, Τμήμα Φαρμακευτικής, Ε.Κ.Π.Α.
Κυριάκος Κυπραίος, Καθηγητής, Τμήμα Ιατρικής, Πανεπιστήμιο Πατρών
Χαράλαμπος Αντωνιάδης, Καθηγητής, Radcliffe Department of Medicine, University of Oxford
Κωνσταντίνος Δροσάτος, Αναπληρωτής Καθηγητής, Lewis Katz School of Medicine, Τemple University
Απόστολος Κλινάκης, Ερευνητής Α’, Ίδρυμα Ιατροβιολογικών Ερευνών, Ακαδημίας Αθηνών
Τριαντάφυλλος Χαβάκης, Καθηγητής, Faculty of Medicine, Technische Universität Dresden
Original Title:
Ρύθμιση του μεταβολισμού από το υδρόθειο
Translated title:
The role of hydrogen sulfide in metabolism
Summary:
Obesity is a multifactorial, chronic disease, resulting from excessive fat accumulation. It is directly related to multiple diseases and considered as one of the leading causes of death. Therefore, it’s prevention and treatment are of great importance in modern western societies. Hydrogen sulfide (H2S) is an endogenously produced signaling molecule with multiple roles in homeostasis and disease. H2S is synthesized by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfutransferase (MPST). Herein, we investigated the role of H2S in the development and treatment of obesity using genetic and pharmacological approaches.
Tο determine the expression of H2S-producing enzymes in adipose tissues of obese subjects, wild-type (WT) mice fed a chow (CD) οr a high fat diet (HFD) for 16 weeks and subcutaneous white adipose tissue (iWAT), epididymal white adipose tissue (gWAT) and interscaptular brown adipose tissue (iBAT) were isolated and used for western blot analysis. Although no differences were observed in CBS and CSE expression, MPST protein levels were reduced in all three adipose tissues of HFD mice. In line with this, H2S concentration was lower in white adipose tissue of obese mice.
To further investigate the role of the MPST enzyme in weight gain, mice with global deletion of Mpst (Mpst-/-) were used. Young Mpst-/- mice fed a high fat diet gained more weight than WT animals. Moreover, they exhibited decreased O2 consumption, CO2 production and metabolic rate, as well as impaired glucose/insulin tolerance. The weight of gWAT and iBAT remained unaltered after the deletion of Mpst, however increased mass and adipocyte size was observed in iWAT of Mpst-/- HFD mice. Interestingly, aged normal chow-fed Mpst-/- also presented an overweight phenotype besides with hypertrophic adipocytes and increased mass of inguinal white fat. Whole transcriptome analysis, performed in iWAT of WT and Mpst-/- HFD mice, provided evidence for upregulation of inflammatory mediators and downregulation of mitochondrial respiratory chain subunits and translocase of outer/inner membrane (ΤΙΜ/ΤΟΜ) components in adipose tissue of deficient mice. Attenuated expression of several TIM/TOM subunits, hampered the translocation of nucleus-encoded mitochondrial proteins and was associated with suppressed levels of TCA and β-oxidation metabolites, indicating the reduced function of the mitochondrial translocase in iWAT of Μpst-/- HFD mice. Genetic and pharmacological inhibition of adipocyte TIM/TOM complex enhanced lipid accumulation, underlining its crucial role in fatty acids degradation and weight gain. Hypoxia conditions inhibited the gene expression of several TIM/TOM components in adipocytes. Similar results observed by HIF1α activation. Nuclear HIF1α was more abundant in inguinal white fat of Mpst-/- HFD mice. Chromatin immunoprecipitation in iWAT of deficient mice, demonstrated that several of the differentially expressed genes between two genotypes, including TIM/TOM and respiratory chain subunits, are HIF1α targets. HIF1α binding to the Tomm6 and Tomm7 promoter was confirmed.
Therapeutic administration of the polysulfide donor SG1002 reversed the changes in weight gain, adipocyte size, metabolic rate and glucose tolerance in obese mice. Furthermore, reduced body weight of obese mice was also detected in the presence of the donor Na2S3. Taken together the above data provide evidence that MPST controls mitochondrial metabolic functions and has profound effects on adipose tissue biology. MPST-regulated pathways offer novel drug targets for obesity.
Main subject category:
Science
Other subject categories:
Health Sciences
Keywords:
obesity, adipose tissue, hydrogen sulfide, 3-mercaptopyruvate sulfurtransferase, mitochondrial translocase, mitochondria, hypoxia-inducible transcription factor 1α
Number of references:
260
