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Mfn1 Deficiency in the Liver Protects Against Diet-Induced

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Mfn1 Deficiency in the Liver Protects Against Diet-Induced 3552 Diabetes Volume 65, December 2016 Sameer S. Kulkarni,1 Magali Joffraud,1 Marie Boutant,1 Joanna Ratajczak,1,2 Arwen W. Gao,3 Catherine Maclachlan,2 Maria Isabel Hernandez-Alvarez,4,5,6 Frédéric Raymond,1 Sylviane Metairon,1 Patrick Descombes,1 Riekelt H. Houtkooper,3 Antonio Zorzano,4,5,6 and Carles Cantó1,2 Mfn1 Deficiency in the Liver Protects Against Diet-Induced Insulin Resistance and Enhances the Hypoglycemic Effect of Metformin Diabetes 2016;65:3552–3560 | DOI: 10.2337/db15-1725 Mitochondrial function can be influenced by mitochon- cellular and organismal energy homeostasis (1). Not sur- drial shape and connectivity with other cellular organ- prisingly, mitochondrial dysfunction is a hallmark of mul- elles through fusion and fission processes. Disturbances tiple metabolic and age-related complications, including in mitochondrial architecture and mitochondrial fusion- insulin resistance and type 2 diabetes (2). A fascinating related genes are observed in situations of type 2 diabetes feature of mitochondria is their ability to modulate their and obesity, leading to a highly fissioned mitochondri- connectivity and architecture, from elongated to punctu- al network. To directly test the effect of reduced mito- ated shapes, through fusion and fission processes (1,3). chondrial fusion on hepatic metabolism, we generated Mitochondrial fusion and fission cycles are believed to fi Mfn1 mice with a liver-speci cdeletionofthe gene balance mitochondrial bioenergetics functions with the (Mfn1LKO) and monitored their energy homeostasis, mi- removal of damaged mitochondria (1,3). Rapid changes tochondrial function, and susceptibility to diet-induced in- METABOLISM in mitochondrial shape take place in several cellular con- sulin resistance. Livers from Mfn1LKO mice displayed a ditions, including cellular proliferation (3) and differenti- highly fragmented mitochondrial network. This was ation (4) and in response to nutrient and hormonal inputs coupled to an enhanced mitochondrial respiration capac- – ity and a preference for the use of lipids as the main (5 7). energy source. Although Mfn1LKO mice are similar to Mitochondrial outer membrane fusion in mammalian control mice fed a low-fat diet, they are protected against cells is controlled by the mitofusin 1 and 2 (Mfn1 and insulin resistance induced by a high-fat diet. Importantly, Mfn2) proteins (3). Despite the high homology between Mfn1 deficiency increased complex I abundance and Mfn1 and Mfn2, these proteins play different noncom- sensitized animals to the hypoglycemic effect of met- plementary roles, as demonstrated by germline deletion formin. Our results suggest that targeting Mfn1 could of Mfn1 or Mfn2 resulting in embryonic lethality (8). provide novel avenues to ameliorate glucose homeo- Most evidence to date indicates that Mfn1 activity is stasis in obese patients and improve the effectiveness mostly devoted to mediating contacts between mitochon- of metformin. dria, whereas Mfn2 can also influence the tethering of mitochondria with other organelles, such as the endoplas- mic reticulum (ER) (3,9). In line with this, mouse embry- Mitochondria are the powerhouses of the cell, converting onic fibroblasts (MEFs) devoid of Mfn1 or Mfn2 failed to nutrients into usable and storable energy in the form of display the networks of long extended mitochondrial tu- ATP and therefore playing a critical role in maintaining bules that characterize wild-type (WT) MEFs (8). The 1Nestlé Institute of Health Sciences, Lausanne, Switzerland Corresponding author: Carles Cantó, [email protected]. 2 École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Received 18 December 2015 and accepted 5 September 2016. 3Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, This article contains Supplementary Data online at http://diabetes the Netherlands .diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1725/-/DC1. 4Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain © 2016 by the American Diabetes Association. Readers may use this article as 5Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat long as the work is properly cited, the use is educational and not for profit, and the de Barcelona, Barcelona, Spain work is not altered. More information is available at http://www.diabetesjournals 6Instituto de Salud Carlos III, CIBERDEM, Madrid, Spain .org/content/license. diabetes.diabetesjournals.org Kulkarni and Associates 3553 relevance of mitofusins in metabolic homeostasis initially glucose after an intraperitoneal injection of 2 g/kg glucose came from studies demonstrating that Mfn2 expression after an overnight fast. Insulin tolerance was measured by was dramatically decreased in the skeletal muscle from injecting insulin (0.75 units/kg for HFD-fed mice) after a obese subjects and subjects with type 2 diabetes in asso- 6-h fast. Plasma insulin was determined in heparinized ciation with a fragmented mitochondrial network (10). plasma samples using specific ELISA kits (EMD Millipore Liver-specific Mfn2 deficiency in mice increases the sus- Corp.). Animals were sacrificed at 13:00 after a 6-h fast. ceptibility to develop insulin resistance even under feed- Blood samples were collected in heparinized tubes, and ing with a regular chow diet (11). This glucose intolerance plasma was isolated after centrifugation. Tissues were col- was partly attributed to an increased hepatic gluconeogene- lected and flash frozen in liquid nitrogen. sis, in line with an increased expression of gluconeogenic Cell Culture and Immunohistochemistry enzymes, including PEPCK and glucose 6-phosphatase MEFs were cultured in DMEM (4.5 g/L glucose) supple- (G6Pase), and of transcriptional regulators of gluconeogene- mented with 10% FBS, Penstrep (1%), nonessential amino sis, such as the peroxisome proliferator–activated receptor g acids (1%), sodium pyruvate (1%), and L-glutamine (1%). coactivator 1a (PGC-1a) (11). This, in turn, was consequent For immunofluorescence assays, MEFs were fixed with 4% to enhanced ER stress in response to Mfn2 deletion (11). paraformaldehyde, and then mitochondria were visualized Given the significant role of Mfn2 in the maintenance by staining with anti-Tom20 antibody or by overexpress- of ER homeostasis, it was not clear to what extent deficient ing mitochondrially targeted Mito-DsRed protein. Nuclei mitochondrial fusion per se contributes to the phenotypes were stained with DAPI. For the Mfn1 recovery experi- observed in the Mfn2-deficient model. To address this ment, Myc-tagged Mfn1-overexpressing plasmids were a question, we created a mouse line with liver-specific gift from David Chan. deletion of Mfn1 (Mfn1LKO). The deletion of Mfn1 led to a dramatically fragmented mitochondrial network and Mitochondrial Isolation enhanced lipid droplet size. Surprisingly, Mfn1LKO mice Mitochondria were freshly isolated from mouse livers as displayed a higher preference for lipid use as energy previously described (12). Full details can be found in the substrate and increased hepatic mitochondrial function. Supplementary Data. These elements granted Mfn1LKO mice protection against Respirometry Studies high-fat diet (HFD)-induced glucose intolerance and Respirometry studies were performed in isolated mito- insulin resistance, despite similar body weight gain. chondria, liver homogenates, or permeabilized extensor Furthermore, HFD-fed Mfn1LKO mice were more sensitive digitorum longus muscle fibers using high-resolution to the hypoglycemic effect of metformin. Our findings respirometry (Oroboros Oxygraph-2k; Oroboros Instru- illustrate how the deletion of Mfn1 and Mfn2 leads to very ments, Innsbruck, Austria).Respirometryanalysesin opposite effects on liver metabolism and that selectively permeabilized muscle fibers and liver homogenates were targeting Mfn1 could provide refined ways to improve performed as previously described (13). Full details on insulin resistance and type 2 diabetes. the buffers and methods used for respirometry analyses RESEARCH DESIGN AND METHODS in isolated mitochondria can be found in the Supple- All animal experiments were performed according to na- mentary Data. tional Swiss and European Union ethical guidelines and Statistical Analyses approved by the local Animal Experimentation Committee Statistical analyses were performed with Prism software under licenses VD 2570. (GraphPad). Differences between two groups were analyzed t P , Animal Care using the Student test (two-tailed, a 0.05 was con- fi 6 Unless otherwise specified, mice were kept in a standard sidered signi cant). Data are expressed as means SEM. temperature- and humidity-controlled environment with a Additional statistical methods can be found in the Supple- 12:12-h light-dark cycle. Mice had access to nesting mentary Data. material and were provided with ad libitum access to water RESULTS and a commercial low-fat diet (LFD) or HFD (D12450J and D12492, respectively, from Research Diets Inc.). Hepatic Deletion of Mfn1 Leads to a Preferential Use of Lipids as the Energy Source Animal Phenotyping Mfn1LKO mice were generated by crossing Mfn1loxP/loxP Mice were weighed and food consumption was measured mice (14) backcrossed to a C57BL/6 background (control each week on the same day. Body composition was mice) with mice expressing the Cre recombinase under the determined by EchoMRI (Echo Medical Systems, Houston, albumin promoter (15). This led to a complete ablation of TX), and VO2, respiratory exchange ratios
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