A PPARγ-Bnip3 Axis Couples Adipose Mitochondrial Fusion-Fission Balance to Systemic Insulin Sensitivity.
Aberrant mitochondrial fission plays a pivotal role in the pathogenesis of skeletal muscle insulin resistance. However, fusion-fission dynamics are physiologically regulated by inherent tissue-specific and nutrient-sensitive processes that may have distinct or even opposing effects with respect to insulin sensitivity. Based on a combination of mouse population genetics and functional in vitro assays, we describe here a regulatory circuit in which peroxisome proliferator-activated receptor γ (PPARγ), the adipocyte master regulator and receptor for the thiazolidinedione class of antidiabetic drugs, controls mitochondrial network fragmentation through transcriptional induction of Bnip3. Short hairpin RNA-mediated knockdown of Bnip3 in cultured adipocytes shifts the balance toward mitochondrial elongation, leading to compromised respiratory capacity, heightened fatty acid β-oxidation-associated mitochondrial reactive oxygen species generation, insulin resistance, and reduced triacylglycerol storage. Notably, the selective fission/Drp1 inhibitor Mdivi-1 mimics the effects of Bnip3 knockdown on adipose mitochondrial bioenergetics and glucose disposal. We further show that Bnip3 is reciprocally regulated in white and brown fat depots of diet-induced obesity and leptin-deficient ob/ob mouse models. Finally, Bnip3(-/-) mice trade reduced adiposity for increased liver steatosis and develop aggravated systemic insulin resistance in response to high-fat feeding. Together, our data outline Bnip3 as a key effector of PPARγ-mediated adipose mitochondrial network fragmentation, improving insulin sensitivity and limiting oxidative stress.
Department of Medical Biochemistry, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
Marc J
MJ
Tol
Department of Medical Biochemistry, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
Roelof
R
Ottenhoff
Department of Medical Biochemistry, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
Marco
M
van Eijk
Department of Medical Biochemistry, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
Noam
N
Zelcer
Department of Pathology, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
Jan
J
Aten
Department of Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY.
Sander M
SM
Houten
Department of Human Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
Dirk
D
Geerts
Department of Medical Biochemistry, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
Cindy
C
van Roomen
Department of Medical Biochemistry, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
Marlou C
MC
Bierlaagh
Department of Medical Biochemistry, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
Saskia
S
Scheij
Department of Medical Biochemistry, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
Marten A
MA
Hoeksema
Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
Johannes M
JM
Aerts
Section of Endocrinology and Metabolism, Departments of Internal Medicine & Cell Biology, Yale University School of Medicine, New Haven, CT.
Jonathan S
JS
Bogan
Centre for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO.
Gerald W
GW
Dorn
Department of Medical Biochemistry, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY carmen.argmann@mssm.edu a.j.verhoeven@amc.uva.nl.
Carmen A
CA
Argmann
Department of Medical Biochemistry, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands carmen.argmann@mssm.edu a.j.verhoeven@amc.uva.nl.
Arthur J
AJ
Verhoeven
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D005260:Female; D005947:Glucose / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000235:genetics / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D015531:Radioimmunoprecipitation Assay; D020133:Reverse Transcriptase Polymerase Chain Reaction
C508686:BNip3 protein, mouse; D007328:Insulin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D047495:PPAR gamma; D005947:Glucose