Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis. (28th October 2020)

• Record Type: Journal Article
• Authors: Garcia, Bruna M; Machado, Thiago S; Carvalho, Karen F; Nolasco, Patrícia; Nociti, Ricardo P; del Collado, Maite; Capo Bianco, Maria J D; Grejo, Mateus P; Augusto Neto, José Djaci; Sugiyama, Fabrícia H C; Tostes, Katiane; Pandey, Anand K; Gonçalves, Luciana M; Perecin, Felipe; Meirelles, Flávio V; Ferraz, José Bento S; Vanzela, Emerielle C; Boschero, Antônio C; Guimarães, Francisco E G; Abdulkader, Fernando; Laurindo, Francisco R M; Kowaltowski, Alicia J; Chiaratti, Marcos R
• Is Part Of: Molecular human reproduction. Volume 26:Number 12(2020)
• Page Start: 938
• Page End: 952
• Publication Date: 2020-10-28
• Subjects: oocyte -- mitochondria dynamics -- MFN2 -- mitochondria -- endoplasmic reticulum -- MERC -- mtDNA -- obesity -- diabetes -- metabolic diseases; Human reproduction -- Molecular aspects -- Periodicals; Electronic journals; 612.6
• DOI: 10.1093/molehr/gaaa071
• Languages: English
• ISSNs: 1360-9947

Abstract

Abstract: Offspring born to obese and diabetic mothers are prone to metabolic diseases, a phenotype that has been linked to mitochondrial dysfunction and endoplasmic reticulum (ER) stress in oocytes. In addition, metabolic diseases impact the architecture and function of mitochondria-ER contact sites (MERCs), changes which associate with mitofusin 2 (MFN2) repression in muscle, liver and hypothalamic neurons. MFN2 is a potent modulator of mitochondrial metabolism and insulin signaling, with a key role in mitochondrial dynamics and tethering with the ER. Here, we investigated whether offspring born to mice with MFN2-deficient oocytes are prone to obesity and diabetes. Deletion of Mfn2 in oocytes resulted in a profound transcriptomic change, with evidence of impaired mitochondrial and ER function. Moreover, offspring born to females with oocyte-specific deletion of Mfn2 presented increased weight gain and glucose intolerance. This abnormal phenotype was linked to decreased insulinemia and defective insulin signaling, but not mitochondrial and ER defects in offspring liver and skeletal muscle. In conclusion, this study suggests a link between disrupted mitochondrial/ER function in oocytes and increased risk of metabolic diseases in the progeny. Future studies should determine whether MERC architecture and function are altered in oocytes from obese females, which might contribute toward transgenerational transmission of metabolic diseases.