Insulin resistance

Insulin resistance (IR) is a pathological condition in which cells either fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood sugar). Insulin is released by the pancreas in response to carbohydrates consumed in the diet. In states of insulin resistance, the same amount of insulin does not have the same effect on glucose transport and blood sugar levels. There are many causes of insulin resistance and the underlying process is still not completely understood. Risk factors for insulin resistance include obesity, sedentary lifestyle, family history of diabetes, various health conditions, and certain medications. Insulin resistance is considered a component of the metabolic syndrome. There are multiple ways to measure insulin resistance such as fasting insulin levels or glucose tolerance tests, but these

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 nicotinamide riboside kinases in mammalian NAD⁺ metabolism

Joanna Ratajczak

NAD+ has emerged as a central metabolic node and an important co-substrate for the activity of various enzymes, including the protein deacetylase SIRT1. Different strategies to increase NAD+ bioavailability have been shown to boost SIRT1 activity, which results in protection against metabolic disease, neurodegenerative disorders and certain types of cancer. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have recently been discovered as new NAD+ precursors. Recent studies have shown that dietary supplementation with NR or NMN prevented against high-fat diet-induced body weight gain. However, the physiological role of NR in mammalian metabolism remains largely unexplored. In this project, we focused on the first step of NR metabolism â the phosphorylation of NR by nicotinamide riboside kinases (NRK1 and NRK2). We have investigated the role of NRKs in the metabolism of NAD+ precursors and mammalian physiology in vivo. The results obtained indicate that NRKs are the rate-limiting and essential step for NR- and NMN-driven NAD+ synthesis in hepatocytes and that NMN has to be extracellularly converted to NR for its use as an NAD+ precursor. Accordingly, animals lacking NRK1 have defects in NR/NMN utilization. We demonstrated that effective NR utilization is key for the maintenance of metabolic homeostasis as NRK1 whole-body KO mice display numerous alterations in glucose and lipid management. Using NRK1 liver-specific KO mice, we demonstrate that NRK1 is required to maintain hepatic NAD+ levels and mitochondrial function upon high-fat feeding. Consequently, NRK1LKO mice are sensitized to diet-induced glucose intolerance and insulin resistance. Finally, we show that both isoforms of NRK are redundant in mediating NR/NMN effects in muscle. Hence, this work identifies NRKs as a novel valuable target in the fight against metabolic disease and indicates that the regulation of NRK will enable us to find novel ways of enhancing NAD+ availability. Moreover, it has unveiled a critical role of NRK1 for the metabolism of diverse forms of Vitamin B3 and highlights how circulating NR is key to preserve metabolic health upon dietary challenges.

EPFL2017

The role of nicotinamide riboside kinases in mammalian NAD⁺ metabolism

Joanna Ratajczak

EPFL2017

Crosstalk between Drp1 phosphorylation sites during mitochondrial dynamics and metabolic adaptation

Miriam Valera Alberni

EPFL2020

Crosstalk between Drp1 phosphorylation sites during mitochondrial dynamics and metabolic adaptation

The role of nicotinamide riboside kinases in mammalian NAD⁺ metabolism

Reduced oxidative capacity in macrophages results in systemic insulin resistance

The role of nicotinamide riboside kinases in mammalian NAD⁺ metabolism

Reduced oxidative capacity in macrophages results in systemic insulin resistance

Crosstalk between Drp1 phosphorylation sites during mitochondrial dynamics and metabolic adaptation