Metabolism | EPFL Graph Search

Metabolism (məˈtæbəlɪzəm, from μεταβολή metabolē, "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the conversion of food to building blocks for proteins, lipids, nucleic acids, and some carbohydrates; and the elimination of metabolic wastes. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, and respond to their environments. The word metabolism can also refer to the sum of all chemical reactions that occur in living organisms, including digestion and the transportation of substances into and between different cells, in which case the above described set of reactions within the cells is called intermediary (or intermediate) metabolism. Metabolic reactions may be categorized as catabolic – the breaking down of compounds (for example, of glucose to pyruvate by cellular respiration); o

Genetic, metabolic, and molecular insights into the diverse outcomes of diet-induced obesity in mouse

Alexis Maximilien Bachmann

Overweight and obesity are increasingly common public health issues worldwide, leading to a wide range of diseases from metabolic syndrome to steatohepatitis and cardiovascular diseases. While the increase in the prevalence of obesity is partly attributable to changes in lifestyle (i.e. increased sedentarity and changes in eating behaviour), the metabolic and clinical impacts of these obesogenic conditions varies between sexes and genetic backgrounds. The conception of personalised treatments of obesity and its complications require a thorough understanding of the diversity of responses to environmental stimuli such as high-fat diet intake. In this thesis, by analysing nine genetically diverse mouse strains, we show that much like humans, mice respond to high-fat diet in a genetic- and sex-dependent manner. Physiological and molecular responses to high-fat diet are associated with the expression of genes involved in immunity and mitochondrial function. Finally, we find that mitochondrial function and mitochondrial supercomplex assembly may explain part of the diversity of physiological responses. By exploring the complex interactions between genetics and metabolic phenotypes via gene expression and molecular traits, we shed light on the importance of genetic background and sex in determining metabolic outcomes. In addition to providing the community with an extensive resource for optimizing future experiments, this work serves as an exemplary design for more generalizable translational studies.

EPFL2021

Crosstalk between Drp1 phosphorylation sites during mitochondrial dynamics and metabolic adaptation

Miriam Valera Alberni

Mitochondria are highly dynamics organelles that undergo coordinated cycles of fission and fusion, referred to as mitochondrial dynamics. Mitochondrial dynamics regulate mitochondrial bioenergetics and allow cells to adapt to changing cellular stresses and physiological challenges. The balance between different GTPase enzymes dictates the shift from interconnected tubular networks to fragmented individual units. Among them, mitochondrial fission is regulated by the mitochondrial fission orchestrator, Drp1. Drp1 function is modulated by post-translational modifications, of which the phosphorylation at two specific sites have gained most attention. Drp1 phosphorylation at the S579 site results in Drp1 recruitment to mitochondria to promote fission, whereas the research on the role of the Drp1 S600 phosphorylation have yielded contradictory results on whether it promotes fission or fusion. Importantly, the crosstalk and physiological impact of these phosphorylations is poorly understood. In this project, we focused first on elucidating the interplay between Drp1 S600 and Drp1 S579 phosphorylations. We described how Drp1 S600 phosphorylation promotes S579 phosphorylation by protecting against its dephosphorylation. The activation at both S600 and S579 sites is required to, then, promote mitochondrial fragmentation. To explore the physiological relevance of these phosphorylations, we generated a Drp1 S600A knock-in (Drp1KI) mouse model. Drp1KI mice displayed enhanced lipid oxidation rates and respiratory capacity, granting improved glucose tolerance and thermogenic capacity upon high-fat feeding. Housing mice at thermoneutrality blunted these differences, suggesting a role for the brown adipose tissue in the protection of Drp1KI mice against metabolic damage. Therefore, this work unveils for the first time the crosstalk between Drp1 phosphorylation sites and their relationship to impact on mitochondrial architecture. Moreover, we demonstrate that targeting the Drp1 S600 site can grant protection against diet-induced insulin resistance, suggesting that the modulation of these phosphorylations could be used in the treatment and prevention of metabolic diseases.

EPFL2020

The role of the transcriptional regulator BCL6 in adipose tissue development and remodeling

Teresa Didonna

The adipose tissue is increasingly recognized for the important role it plays in various diseases and pathological conditions, such as obesity, diabetes, cardiovascular diseases, osteoporosis, cancer, and aging. Despite its long-held reputation for being a simple fat storage tissue, we now know the adipose tissue is a singular organ playing a crucial role in whole-body metabolism and energy homeostasis. Understanding the development and functioning of adipose tissue and, in particular, of its structural and functional fat depots, is crucial to understanding human health and disease, and can pave the way for personalized therapeutic and preventive approaches. Transcription factors are key regulators of adipose tissue biogenesis, development, and responses to changes in environmental stimuli such as feeding, fasting, and exercise. The transcription repressor BCL6 - well known in immunology and cancer - has been recently linked to adipogenesis and metabolism. In the context of this thesis, in order to better understand the role of BCL6 in adipose tissue development and remodeling, we sought to further investigate the physiological function of BCL6 in white and brown adipose tissue. We developed and characterized a fat-specific conditional knockout mouse model for Bcl6 (Bcl6 FKO), and a Pdgfra-Cre driver was used to obtain in vivo ablation of Bcl6 in adipogenic precursors and stem cells (ASPCs). We discovered that ablation of Bcl6 in adipocyte precursors has a major impact on white fat mass and its distribution in the bodies of mice. Moreover, being fed a standard and a high-fat diet has a prominent effect on visceral adipose tissue, the mass of which was significantly reduced compared to that of control mice. Additionally, Bcl6 FKO mice did not demonstrate sensitivity to high-fat diet-induced mass gain and related comorbidities, such as hepatic steatosis and glucose-homeostasis alterations. The increased number of adipocytes observed in the gonadal adipose tissue occurred without increasing overall adiposity and body weight compared to control mice under a high-caloric diet regime. In conclusion, Bcl6 FKO mice represent a lean mouse model with a healthy balance between subcutaneous and visceral white adipose tissue depots. BCL6 could be an interesting adipose-specific target for therapeutic interventions in the context of obesity and related metabolic dysfunctions.

EPFL2019