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A PPARγ-Bnip3 Axis Couples Adipose Mitochondrial Fusion-Fission Balance to Systemic Insulin Sensitivity
- Source :
- Diabetes, 65(9), 2591-2605. American Diabetes Association Inc., Tol, M J, Ottenhoff, R, van Eijk, M, Zelcer, N, Aten, J, Houten, S M, Geerts, D, van Roomen, C, Bierlaagh, M C, Scheij, S, Hoeksema, M A, Aerts, J M, Bogan, J S, Dorn, G W, Argmann, C A & Verhoeven, A J 2016, ' A PPARγ-Bnip3 Axis Couples Adipose Mitochondrial Fusion-Fission Balance to Systemic Insulin Sensitivity ', Diabetes, vol. 65, no. 9, pp. 2591-605 . https://doi.org/10.2337/db16-0243, Diabetes, 65(9), 2591-605. American Diabetes Association Inc., Diabetes
- Publication Year :
- 2016
- Publisher :
- American Diabetes Association, 2016.
-
Abstract
- 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.
- Subjects :
- Male
0301 basic medicine
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Adipose tissue
Peroxisome proliferator-activated receptor
Mitochondrion
Mitochondrial Dynamics
Mice
chemistry.chemical_compound
0302 clinical medicine
Adipocyte
Adipocytes
Insulin
Mice, Knockout
chemistry.chemical_classification
Reverse Transcriptase Polymerase Chain Reaction
Cell Differentiation
Immunohistochemistry
Mitochondria
mitochondrial fusion
Female
Mitochondrial fission
Radioimmunoprecipitation Assay
medicine.medical_specialty
Immunoblotting
Biology
Cell Line
Mitochondrial Proteins
03 medical and health sciences
Insulin resistance
3T3-L1 Cells
Internal medicine
Internal Medicine
medicine
Animals
Obesity
Membrane Proteins
medicine.disease
Mice, Inbred C57BL
PPAR gamma
Metabolism
Glucose
030104 developmental biology
Endocrinology
Microscopy, Fluorescence
chemistry
Insulin Resistance
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 65
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....668a2d27f947d2f9243e15a4a3927da6