Regulation of energy expenditure by mitochondrial dynamics in brown adipose tissue from subcellular to whole body level

Obesity is a disorder of energy imbalance in which energy intake exceeds energy expenditure (EEX). Brown adipose tissue (BAT) is unique in that it can increase whole body EEX when it is adrenergically activated. The thermogenic capacity of BAT is mediated by mitochondrial uncoupling through the activation of Uncoupling Protein 1 which uncouple respiration from ATP production. Mitochondria is a dynamic organelle that undergo continuous cycles of fusion and fission. Alteration in mitochondrial dynamics correlates with changes in energy efficiency in different cell types; however, its role in regulating EEX in BAT has not been investigated. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically-induced changes in EEX in BAT. Norepinephrine (NE) induces mitochondrial fragmentation in brown adipocytes (BA) though posttranslational modifications - phosphorylation and proteolytic cleavage -of mitochondrial dynamic proteins. NE-induced EEX is reduced in fission-deficient brown adipocytes while forced mitochondrial fragmentation increases the respiration in response to exogenous free fatty acids (FFAs) indicating increase in EEX. We further investigated whether forced mitochondrial fragmentation in BAT could be utilized as an approach to increase whole body EEX is response to FFA in vivo. We found that a mouse model with forced mitochondrial fragmentation in BAT (BAT-Mitofusin2-KO) gained less body weight and less fat mass and remained more glucose tolerant and insulin sensitive under high fat diet (HFD) compared to the wild type. Additionally, FFA oxidation was enhanced in BAT-Mitofusin2-KO mice indicated by lower respiratory exchange ratio. We also found that subcellular heterogeneity in dynamics leads to the generation of subpopulations of mitochondria with diverse bioenergetics characteristics within the same cell. We described that a subpopulation of mitochondria surrounding the lipid droplet in BA had higher ATP synthesis capacity, supported by higher ATP synthase protein expression and elongated morphology. We suggest that this subpopulation of mitochondria is responsible for addressing the ATP demand of the BA when it is not activated. In conclusion, changes to mitochondrial dynamics are required for BAT thermogenic activity and for the control of EEX efficiency from sub-cellular to the whole body level. Additionally, mitochondrial dynamics in BAT can regulate fatty acid oxidation.2018-06-15T00:00:00

Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis.

BAT-controlled thermogenic activity is thought to be required for its capacity to prevent the development of insulin resistance. This hypothesis predicts that mediators of thermogenesis may help prevent diet-induced insulin resistance. We report that the mitochondrial fusion protein Mitofusin 2 (Mfn2) in BAT is essential for cold-stimulated thermogenesis, but promotes insulin resistance in obese mice. Mfn2 deletion in mice through Ucp1-cre (BAT-Mfn2-KO) causes BAT lipohypertrophy and cold intolerance. Surprisingly however, deletion of Mfn2 in mice fed a high fat diet (HFD) results in improved insulin sensitivity and resistance to obesity, while impaired cold-stimulated thermogenesis is maintained. Improvement in insulin sensitivity is associated with a gender-specific remodeling of BAT mitochondrial function. In females, BAT mitochondria increase their efficiency for ATP-synthesizing fat oxidation, whereas in BAT from males, complex I-driven respiration is decreased and glycolytic capacity is increased. Thus, BAT adaptation to obesity is regulated by Mfn2 and with BAT-Mfn2 absent, BAT contribution to prevention of insulin resistance is independent and inversely correlated to whole-body cold-stimulated thermogenesis

Mitochondria Bound to Lipid Droplets Have Unique Bioenergetics, Composition, and Dynamics that Support Lipid Droplet Expansion

Mitochondria associate with lipid droplets (LDs) in fat-oxidizing tissues, but the functional role of these peridroplet mitochondria (PDM) is unknown. Microscopic observation of interscapular brown adipose tissue reveals that PDM have unique protein composition and cristae structure and remain adherent to the LD in the tissue homogenate. We developed an approach to isolate PDM based on their adherence to LDs. Comparison of purified PDM to cytoplasmic mitochondria reveals that (1) PDM have increased pyruvate oxidation, electron transport, and ATP synthesis capacities; (2) PDM have reduced β-oxidation capacity and depart from LDs upon activation of brown adipose tissue thermogenesis and β-oxidation; (3) PDM support LD expansion as Perilipin5-induced recruitment of mitochondria to LDs increases ATP synthase-dependent triacylglyceride synthesis; and (4) PDM maintain a distinct protein composition due to uniquely low fusion-fission dynamics. We conclude that PDM represent a segregated mitochondrial population with unique structure and function that supports triacylglyceride synthesis

ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity

Although the role of hydrophilic antioxidants in the development of hepatic insulin resistance and nonalcoholic fatty liver disease has been well studied, the role of lipophilic antioxidants remains poorly characterized. A known lipophilic hydrogen peroxide scavenger is bilirubin, which can be oxidized to biliverdin and then reduced back to bilirubin by cytosolic biliverdin reductase. Oxidation of bilirubin to biliverdin inside mitochondria must be followed by the export of biliverdin to the cytosol, where biliverdin is reduced back to bilirubin. Thus, the putative mitochondrial exporter of biliverdin is expected to be a major determinant of bilirubin regeneration and intracellular hydrogen peroxide scavenging. Here, we identified ABCB10 as a mitochondrial biliverdin exporter. ABCB10 reconstituted into liposomes transported biliverdin, and ABCB10 deletion caused accumulation of biliverdin inside mitochondria. Obesity with insulin resistance up-regulated hepatic ABCB10 expression in mice and elevated cytosolic and mitochondrial bilirubin content in an ABCB10-dependent manner. Revealing a maladaptive role of ABCB10-driven bilirubin synthesis, hepatic ABCB10 deletion protected diet-induced obese mice from steatosis and hyperglycemia, improving insulin-mediated suppression of glucose production and decreasing lipogenic SREBP-1c expression. Protection was concurrent with enhanced mitochondrial function and increased inactivation of PTP1B, a phosphatase disrupting insulin signaling and elevating SREBP-1c expression. Restoration of cellular bilirubin content in ABCB10 KO hepatocytes reversed the improvements in mitochondrial function and PTP1B inactivation, demonstrating that bilirubin was the maladaptive effector linked to ABCB10 function. Thus, we identified a fundamental transport process that amplifies intracellular bilirubin redox actions, which can exacerbate insulin resistance and steatosis in obesity