Mfn1 Deficiency in the Liver Protects Against Diet-Induced Insulin Resistance and Enhances the Hypoglycemic Effect of Metformin.
Mitochondrial function can be influenced by mitochondrial shape and connectivity with other cellular organelles through fusion and fission processes. Disturbances in mitochondrial architecture and mitochondrial fusion-related genes are observed in situations of type 2 diabetes and obesity, leading to a highly fissioned mitochondrial network. To directly test the effect of reduced mitochondrial fusion on hepatic metabolism, we generated mice with a liver-specific deletion of the Mfn1 gene (Mfn1LKO) and monitored their energy homeostasis, mitochondrial function, and susceptibility to diet-induced insulin resistance. Livers from Mfn1LKO mice displayed a highly fragmented mitochondrial network. This was coupled to an enhanced mitochondrial respiration capacity and a preference for the use of lipids as the main energy source. Although Mfn1LKO mice are similar to control mice fed a low-fat diet, they are protected against insulin resistance induced by a high-fat diet. Importantly, Mfn1 deficiency increased complex I abundance and sensitized animals to the hypoglycemic effect of metformin. Our results suggest that targeting Mfn1 could provide novel avenues to ameliorate glucose homeostasis in obese patients and improve the effectiveness of metformin.
Nestlé Institute of Health Sciences, Lausanne, Switzerland.
Sameer S
SS
Kulkarni
Nestlé Institute of Health Sciences, Lausanne, Switzerland.
Magali
M
Joffraud
Nestlé Institute of Health Sciences, Lausanne, Switzerland.
Marie
M
Boutant
Nestlé Institute of Health Sciences, Lausanne, Switzerland.|École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Joanna
J
Ratajczak
Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlands.
Arwen W
AW
Gao
École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Catherine
C
Maclachlan
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, CIBERDEM, Madrid, Spain.
Maria Isabel
MI
Hernandez-Alvarez
Nestlé Institute of Health Sciences, Lausanne, Switzerland.
Frédéric
F
Raymond
Nestlé Institute of Health Sciences, Lausanne, Switzerland.
Sylviane
S
Metairon
Nestlé Institute of Health Sciences, Lausanne, Switzerland.
Patrick
P
Descombes
Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlands.
Riekelt H
RH
Houtkooper
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, CIBERDEM, Madrid, Spain.
Antonio
A
Zorzano
Nestlé Institute of Health Sciences, Lausanne, Switzerland carlos.cantoalvarez@rd.nestle.com.|École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Carles
http://orcid.org/0000-0002-5167-7922
C
Cantó
D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D020558:GTP Phosphohydrolases / Q000172:deficiency* / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism
D007004:Hypoglycemic Agents; D008687:Metformin; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse