A PPARγ-Bnip3 Axis Couples Adipose Mitochondrial Fusion-Fission Balance to Systemic Insulin Sensitivity

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.

Effects of melatonin on fatty liver disease: The role of NR4A1/DNA‐PKcs/p53 pathway, mitochondrial fission, and mitophagy

“…Aside from mitochondrial fission, mitophagy is another catabolic process involving degradation of unnecessary or dysfunctional mitochondria by lysosomes. For Bnip3‐required mitophagy, few references exist describing its role in NAFLD, although several studies have hinted that Bnip3 deficiency aggravates insulin resistance and metabolic syndrome . Based on these, we explored the role of Bnip3‐related mitophagy in NAFLD.…”

Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity

“…On the molecular level, beige or brite adipocytes are characterized by the high mitochondrial content and expression of genes, which decouple the proton gradient from ATP production (Kajimura et al , ). Moreover, recent studies indicate that the induction of mitochondrial fragmentation also promotes decoupling activity in adipocytes, which protects mice from the development of diabetes and fatty liver disease (Wikstrom et al , ; Tol et al , ).…”

Adipose tissue NAD+-homeostasis, sirtuins and poly(ADP-ribose) polymerases -important players in mitochondrial metabolism and metabolic health

“…In HFD induced obese mouse WAT, the protein levels of mitophagy markers including PTEN-induced putative kinase 1 and E3 ubiquitin ligase parkin are increased, indicating increased mitochondrial turnover [40]. In contrast, WAT mRNA levels of the same markers correlate inversely with body weight and positively with insulin sensitivity in mice [42]. Current data on the mitochondrial unfolded protein response pathway are obese WAT is also limited, but expression level of genes in this pathway were decreased in the heavier co-twin of BMI discordant monozygotic twins [43], and increased by treatment with anti-diabetic medication in WAT of obese diabetic mice [41].…”