Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue
Objective: Sex differences in adipose tissue impact metabolic health, but the underlying molecular mechanisms remain unclear. We previously identified a female-specific chr17 trans-eQTL hotspot regulating mitochondrial gene expression in gonadal white adipose tissue (gWAT). Here, we tested whether i...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-10-01
|
| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825001346 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849236011345772544 |
|---|---|
| author | Dorota Kaminska Calvin Pan Laurent Vergnes Ashlyn Ro Gurugowtham Ulaganathan Aldons J. Lusis |
| author_facet | Dorota Kaminska Calvin Pan Laurent Vergnes Ashlyn Ro Gurugowtham Ulaganathan Aldons J. Lusis |
| author_sort | Dorota Kaminska |
| collection | DOAJ |
| description | Objective: Sex differences in adipose tissue impact metabolic health, but the underlying molecular mechanisms remain unclear. We previously identified a female-specific chr17 trans-eQTL hotspot regulating mitochondrial gene expression in gonadal white adipose tissue (gWAT). Here, we tested whether iWAT contributes comparably to sex differences in mitochondrial function and futile cycling. Methods: We analyzed iWAT and gWAT from male and female mice across 58 genetically diverse Hybrid Mouse Diversity Panel (HMDP) strains fed a high-fat, high-sucrose diet. We assessed mitochondrial DNA (mtDNA), oxidative phosphorylation (OXPHOS) and futile cycle gene expression, performed genetic mapping, and measured respiration. Results: In gWAT, females showed higher mtDNA, OXPHOS expression, and a female-specific chr17 trans-eQTL, correlating with metabolic traits. In contrast, iWAT lacked this hotspot and showed higher mtDNA, OXPHOS expression, and respiration in males. Lipid cycling genes (Lipe, Mgll, Pnpla2) were elevated in male iWAT, while Mpc1, Mpc2, and Pck1 were enriched in female gWAT. Ucp1 was higher in female gWAT but not sex-biased in iWAT. Alpl (TNAP), key creatine cycling gene, was upregulated in females in both depots, particularly in iWAT. Conclusions: Female gWAT shows genetically driven mitochondrial regulation linked to metabolic protection, whereas male iWAT has higher mitochondrial content, OXPHOS expression, and respiration. Elevated lipolytic enzymes in male iWAT suggest greater FFA release, while higher pyruvate import and glyceroneogenesis genes in female gWAT favor FFA recycling. Alpl upregulation in females indicates sex-biased UCP1-independent thermogenesis. These depot- and sex-specific signatures reflect distinct metabolic strategies and highlight the need to consider both in adipose research. |
| format | Article |
| id | doaj-art-6f0270b8751f4c14bd923fa2deea12d0 |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-6f0270b8751f4c14bd923fa2deea12d02025-08-20T04:02:31ZengElsevierMolecular Metabolism2212-87782025-10-0110010222710.1016/j.molmet.2025.102227Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissueDorota Kaminska0Calvin Pan1Laurent Vergnes2Ashlyn Ro3Gurugowtham Ulaganathan4Aldons J. Lusis5Department of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Corresponding author.Department of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USADepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USADepartment of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USADepartment of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USADepartment of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Corresponding author. Department of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.Objective: Sex differences in adipose tissue impact metabolic health, but the underlying molecular mechanisms remain unclear. We previously identified a female-specific chr17 trans-eQTL hotspot regulating mitochondrial gene expression in gonadal white adipose tissue (gWAT). Here, we tested whether iWAT contributes comparably to sex differences in mitochondrial function and futile cycling. Methods: We analyzed iWAT and gWAT from male and female mice across 58 genetically diverse Hybrid Mouse Diversity Panel (HMDP) strains fed a high-fat, high-sucrose diet. We assessed mitochondrial DNA (mtDNA), oxidative phosphorylation (OXPHOS) and futile cycle gene expression, performed genetic mapping, and measured respiration. Results: In gWAT, females showed higher mtDNA, OXPHOS expression, and a female-specific chr17 trans-eQTL, correlating with metabolic traits. In contrast, iWAT lacked this hotspot and showed higher mtDNA, OXPHOS expression, and respiration in males. Lipid cycling genes (Lipe, Mgll, Pnpla2) were elevated in male iWAT, while Mpc1, Mpc2, and Pck1 were enriched in female gWAT. Ucp1 was higher in female gWAT but not sex-biased in iWAT. Alpl (TNAP), key creatine cycling gene, was upregulated in females in both depots, particularly in iWAT. Conclusions: Female gWAT shows genetically driven mitochondrial regulation linked to metabolic protection, whereas male iWAT has higher mitochondrial content, OXPHOS expression, and respiration. Elevated lipolytic enzymes in male iWAT suggest greater FFA release, while higher pyruvate import and glyceroneogenesis genes in female gWAT favor FFA recycling. Alpl upregulation in females indicates sex-biased UCP1-independent thermogenesis. These depot- and sex-specific signatures reflect distinct metabolic strategies and highlight the need to consider both in adipose research.http://www.sciencedirect.com/science/article/pii/S2212877825001346iWATgWATMitochondriaMetabolismSex |
| spellingShingle | Dorota Kaminska Calvin Pan Laurent Vergnes Ashlyn Ro Gurugowtham Ulaganathan Aldons J. Lusis Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue Molecular Metabolism iWAT gWAT Mitochondria Metabolism Sex |
| title | Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue |
| title_full | Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue |
| title_fullStr | Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue |
| title_full_unstemmed | Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue |
| title_short | Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue |
| title_sort | genetic and sex specific regulation of mitochondrial function in gonadal and inguinal adipose tissue |
| topic | iWAT gWAT Mitochondria Metabolism Sex |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825001346 |
| work_keys_str_mv | AT dorotakaminska geneticandsexspecificregulationofmitochondrialfunctioningonadalandinguinaladiposetissue AT calvinpan geneticandsexspecificregulationofmitochondrialfunctioningonadalandinguinaladiposetissue AT laurentvergnes geneticandsexspecificregulationofmitochondrialfunctioningonadalandinguinaladiposetissue AT ashlynro geneticandsexspecificregulationofmitochondrialfunctioningonadalandinguinaladiposetissue AT gurugowthamulaganathan geneticandsexspecificregulationofmitochondrialfunctioningonadalandinguinaladiposetissue AT aldonsjlusis geneticandsexspecificregulationofmitochondrialfunctioningonadalandinguinaladiposetissue |