For example, the work of the team led by Benoit Viollet is interested in the protein kinase AMPK (AMP-activated protein kinase) which plays a crucial role as a sensor of the energy state of cells. Thanks to its major role in the regulation of energy homeostasis, and in particular its ability to inhibit anabolic pathways to stimulate catabolic pathways, AMPK appears as a potential therapeutic target for the treatment of metabolic diseases, such as obesity. The Viollet team was able to show the therapeutic interest of pharmacological activation of AMPK in the main metabolic organs such as the liver (1), adipose tissue (2), and skeletal muscle (3), offering new therapeutic perspectives to reduce the pathological consequences of metabolic dysfunctions.
The intestinal microbiota is now considered a key factor in the pathogenesis of obesity. In this context, researchers are working on the role of gastrointestinal tract AMPK in the metabolic dialogue established between the host and its microbiota leading to the beneficial effects induced by changes in the intestinal microbiota (4). The activation of AMPK in the intestine in response to prebiotics or pharmacological compounds such as the anti-diabetic metformin, could thus make it possible to limit the deleterious effects of a diet high in fat and low in dietary fiber and thus to fight effectively against the development of obesity.
The Ute Rogner / Amine Toubal group, in the team led by Agnès Lehuen, is interested in the role of MAIT immune cells during obesity and their interaction with the microbiota. Indeed, these cells recognize ligands of bacterial origin and are preferably located in the intestinal mucosa and the liver. Researchers are investigating the potential link between MAIT cells, inflammation and microbiota imbalance in obesity, using both human samples and animal models. They demonstrated a deleterious role of these cells in the visceral adipose tissue of obese subjects through the production of interleukin 17 (5). Using several mouse models, the team also demonstrated that MAIT cells were involved in intestinal dysbiosis during obesity. Indeed, they are sensitive to the presence of bacterial families associated with intestinal inflammation such as Actinomycetes family. This results in increased intestinal permeability and inflammation favoring the development of type 2 diabetes. Finally, Lehuen’s team demonstrated that MAIT cells could constitute a supposed therapeutic target for limiting the deleterious effects of obesity. Treatment of obese mice with a ligand blocking MAIT cells improves metabolic parameters such as insulin resistance or glucose tolerance (6).
This group is also studying the Bmal2 gene, a key circadian clock gene and candidate in obesity and type 2 diabetes.
The team led by Dr. Ralf Jockers, including the group led by Dr. Julie Dam, is studying the altered function of key regulators in the etiology of obesity. Among these regulators is leptin, a hormone produced by fat tissues, whose gene was the first obesity gene to be discovered. Leptin decreases hunger and mutations in its gene lead to severe obesity in humans.
The Jockers team was one of the first to show that decreases in the localization of the leptin receptor on the cell surface were a key factor in the development of obesity, by studying a regulatory protein (namely Endospanin 1) of leptin receptor. In addition, the Jockers team in collaboration with the team of Dr V. Prévot (Lille) revealed the importance of the communication between the brain and peripheral organs in the regulation of hunger/satiety and the development of fat mass. This collaboration has, for the first time, brought to light a previously unknown gateway for peripheral hormones such as leptin to the hypothalamus, the key center for metabolic integration and eating behavior. This discovery paves the way to understanding the transport of metabolic hormones in the brain and its importance in the development of obesity (7-17).
The Jockers team is currently part of a European Consortium OBESLISK (led by Prof. Philippe Froguel) dedicated to the identification and characterization of new genes contributing to the development of adult and childhood obesity.
This research goes far beyond the walls of Institut Cochin and is naturally integrated into local (Institut Hors Murs Diabète), national (GDR LTinnés, Labex Who am I, Labex Inflamex), and international collaborative networks (European Consortium OBESLISK) to respond at best to this global issue of the treatment of obesity.
References
- Chuang SJ, Johanns M, Pyr Dit Ruys S, Steinberg GR, Kemp BE, Viollet B, Rider MH. AMPK activation by SC4 inhibits noradrenaline-induced lipolysis and insulin-stimulated lipogenesis in white adipose tissue. Biochem J. 2021 Nov 12;478(21):3869-3889. doi: 10.1042/BCJ20210411. PMID: 34668531
- Schmoll D, Ziegler N, Viollet B, Foretz M, Even PC, Azzout-Marniche D, Nygaard Madsen A, Illemann M, Mandrup K, Feigh M, Czech J, Glombik H, Olsen JA, Hennerici W, Steinmeyer K, Elvert R, Castañeda TR, Kannt A. Activation of Adenosine Monophosphate-Activated Protein Kinase Reduces the Onset of Diet-Induced Hepatocellular Carcinoma in Mice. Hepatol Commun. 2020 May 15;4(7):1056-1072. PMID: 32626837
- Lantier L, Williams AS, Williams IM, Guerin A, Bracy DP, Goelzer M, Foretz M, Viollet B, Hughey CC, Wasserman DH. Reciprocity Between Skeletal Muscle AMPK Deletion and Insulin Action in Diet-Induced Obese Mice. Diabetes. 2020 Aug;69(8):1636-1649. PMID: 32439824
- Olivier S, Pochard C, Diounou H, Castillo V, Divoux J, Alcantara J, Leclerc J, Guilmeau S, Huet C, Charifi W, Varin TV, Daniel N, Foretz M, Neunlist M, Salomon BL, Ghosh P, Marette A, Rolli-Derkinderen M, Viollet B. Deletion of intestinal epithelial AMP-activated protein kinase alters distal colon permeability but not glucose homeostasis. Mol Metab. 2021 May;47:101183. PMID: 33548500
- Magalhaes I, Pingris K, Poitou C, Bessoles S, Venteclef N, Kiaf B, Beaudoin L, Da Silva J, Allatif O, Rossjohn J, Kjer-Nielsen L, McCluskey J, Ledoux S, Genser L, Torcivia A, Soudais C, Lantz O, Boitard C, Aron-Wisnewsky J, Larger E, Clément K, Lehuen A. Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J Clin Invest. 2015 Apr;125(4):1752-62. doi: 10.1172/JCI78941. PMID: 25751065; PMCID: PMC4396481.
- Toubal A, Kiaf B, Beaudoin L, Cagninacci L, Rhimi M, Fruchet B, da Silva J, Corbett AJ, Simoni Y, Lantz O, Rossjohn J, McCluskey J, Lesnik P, Maguin E, Lehuen A. Mucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity. Nat Commun. 2020 Jul 24;11(1):3755. doi: 10.1038/s41467-020-17307-0. PMID: 32709874; PMCID: PMC7381641
- Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity. Couturier C, Sarkis C, Séron K, Belouzard S, Chen P, Lenain A, Corset L, Dam J, Vauthier V, Dubart A, Mallet J, Froguel P, Rouillé Y, Jockers R. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19476-81. doi: 10.1073/pnas.0706671104..
- Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Balland E, Dam J, Langlet F, Caron E, Steculorum S, Messina A, Rasika S, Falluel-Morel A, Anouar Y, Dehouck B, Trinquet E, Jockers R, Bouret SG, Prévot V. Cell Metab. 2014 Feb 4;19(2):293-301.
- Anti-obesity phenotypic screening looking to increase OBR cell surface expression. Kim TH, Choi DH, Vauthier V, Dam J, Li X, Nam YJ, Ko Y, Kwon HJ, Shin SH, Cechetto J, Soloveva V, Jockers R. J Biomol Screen. 2014 Jan;19(1):88-99.
- Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Balland E, Dam J, Langlet F, Caron E, Steculorum S, Messina A, Rasika S, Falluel-Morel A, Anouar Y, Dehouck B, Trinquet E, Jockers R, Bouret SG, Prévot V. Cell Metab. 2014 Feb 4;19(2):293-301.
- Endospanin1 affects oppositely body weight regulation and glucose homeostasis by differentially regulating central leptin signaling. Vauthier V, Roujeau C, Chen P, Sarkis C, Migrenne S, Hosoi T, Ozawa K, Rouillé Y, Foretz M, Mallet J, Launay JM, Magnan C, Jockers R, Dam J. Mol Metab. 2016 Nov 3;6(1):159-172.
- [Hypothalamic endospanin 1 dissociates obesity from type 2 diabetes]. Roujeau C, Jockers R, Dam J. Med Sci (Paris). 2018 Apr;34(4):288-291. doi: 10.1051/medsci/20183404003.
- Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions. Roujeau C, Jockers R, Dam J. Neuroendocrinology. 2019;108(2):132-141. doi: 10.1159/000494557. Epub 2018 Oct 16.
- Leptin brain entry via a tanycytic LepR-EGFR shuttle controls lipid metabolism and pancreas function. Duquenne M, Folgueira C, Bourouh C, Millet M, Silva A, Clasadonte J, Imbernon M, Fernandois D, Martinez-Corral I, Kusumakshi S, Caron E, Rasika S, Deliglia E, Jouy N, Oishi A, Mazzone M, Trinquet E, Tavernier J, Kim YB, Ory S, Jockers R, Schwaninger M, Boehm U, Nogueiras R, Annicotte JS, Gasman S, Dam J*, Prévot V*. Nat Metab*. 2021 Aug;3(8):1071-1090. doi: 10.1038/s42255-021-00432-5.
- Castan-Laurell I., Masri B., Valet P. (2018) The apelin/APJ system as a therapeutic target in metabolic diseases. Expert Opin Ther Targets. 23(3):215-225.
- Chaves-Almagro C., Castan-Laurell I., Dray C., Knauf C., Valet P., Masri B. (2015) Apelin receptors: From signaling to antidiabetic strategy. Eur J Pharmacol. 763 (Pt B): 149-59.
- Masri B., Dray C., Knauf C., Valet P., Castan-Laurell I. (2015) Le récepteur de l'apeline: Une voie originale dans la stratégie antidiabétique. Médecine/Sciences. 31(3):275-81.
