title: Mfn2 is critical for brown adipose tissue thermogenic function.
abstract: Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine-tune cellular bioenergetics. Defective mitofusin 2 (Mfn2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin-resistant states. Interestingly, Mfn2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose-specific Mfn2 knockout (Mfn2-adKO) mice, we demonstrate that Mfn2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity and a blunted response to adrenergic stimuli. Importantly, Mfn2 directly interacts with perilipin 1, facilitating the interaction between the mitochondria and the lipid droplet in response to adrenergic stimulation. Surprisingly, Mfn2-adKO mice were protected from high-fat diet-induced insulin resistance and hepatic steatosis. Altogether, these results demonstrate that Mfn2 is a mediator of mitochondria to lipid droplet interactions, influencing lipolytic processes and whole-body energy homeostasis.
authors.affiliation: Nestlé Institute of Health Sciences, Lausanne, Switzerland.
authors.forename: Marie
authors.initials: M
authors.lastname: Boutant
authors.affiliation: Nestlé Institute of Health Sciences, Lausanne, Switzerland.
authors.forename: Sameer S
authors.initials: SS
authors.lastname: Kulkarni
authors.affiliation: Nestlé Institute of Health Sciences, Lausanne, Switzerland.
authors.forename: Magali
authors.initials: M
authors.lastname: Joffraud
authors.affiliation: Nestlé Institute of Health Sciences, Lausanne, Switzerland.|School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Ratajczak
authors.affiliation: Nestlé Institute of Health Sciences, Lausanne, Switzerland.|School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Valera-Alberni
authors.affiliation: Center of PhenoGenomics (CPG), Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Roy
authors.initials: R
authors.lastname: Combe
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.|Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.|Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Antonio
authors.identifier: 0000-0002-1638-0306
authors.initials: A
authors.lastname: Zorzano
authors.affiliation: Nestlé Institute of Health Sciences, Lausanne, Switzerland carlos.cantoalvarez@rd.nestle.com.|School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Carles
authors.identifier: 0000-0002-5167-7922
authors.initials: C
authors.lastname: Cantó
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D020558:GTP Phosphohydrolases / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D000070778:Perilipin-1 / Q000378:metabolism; D011485:Protein Binding; D022722:Thermogenesis
chemical_list: D000070778:Perilipin-1; C000602979:Plin1 protein, mouse; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse
keywords: brown adipose tissue; insulin resistance; lipid droplet; mitochondrial dynamics; mitofusin 2