OPA1 Deletion in Brown Adipose Tissue Improves Thermoregulation and Systemic Metabolism via FGF21

Abstract

Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including proteolytic processing of the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. By deleting OPA1 selectively in BAT (OPA1 BAT KO), we demonstrate that OPA1 is required for cold-induced thermogenesis. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)- dependent manner. BAT-derived FGF21 mediates an adaptive response in OPA1 BAT KO mice, by inducing browning of white adipose tissue (WAT), increasing resting metabolic rates, and improving thermoregulation. However, FGF21 does not mediate the resistance to diet-induced obesity observed in these animals. These findings reveal a requirement for OPA1 in BAT thermogenesis, and uncovers a homeostatic mechanism of BAT-mediated metabolic protection governed by an ATF4-FGF21 axis, that is activated independently of BAT thermogenic function.

LETMD1 is required for mitochondrial structure and thermogenic function of brown adipocytes

“…Cristae morphology is directly affected by normal mitochondria fusion and fission, and it has been shown that deletion of Opa1 and Mfn2, which are both required for mitochondria fusion, cause disrupted cristae formation and abnormal mitochondria structure. 35,[52][53][54] Our findings also correlate with a previous study that observed mitochondria hyperpolarization, decreased ATP production and increased mitochondrial ROS resulting from knockdown of Letmd1 in human macrophage-like cell lines. 38 Although deletion of Letmd1 resulted in blunted mitochondrial function and energy metabolism, it has not been determined whether LETMD1 directly affects UCP1 and thermogenic programs, or if this is just a consequence of the impaired cristae formation.…”

“…33,34 More recently, it has been reported that optic atrophy 1 (OPA1) is required for cold-induced thermogenesis by regulating the balance of mitochondrial fusion and fission. 35 As a result, mitochondrial structure (for example cristae structure) and dynamics (for example fusion and fission) are critical for thermogenesis and energy expenditure. Therefore, identifying novel regulators of mitochondrial function could lead to new strategies to boost BAT thermogenesis.…”

ATF4 Expression in Thermogenic Adipocytes is Required for Cold-Induced Thermogenesis in Mice via FGF21-Independent Mechanisms

“…However, in our recent study, we demonstrated that FGF21 can be induced even when BAT's thermogenic function is dampened, via ATF4 activation (9). ATF4 has been shown to bind to the FGF21 promoter and to induce its transcription in several models (29,30,31).…”

“…Nonetheless, a recent study demonstrated that adult-onset conditional Atf4 deletion in agouti-related peptide neurons in the hypothalamus of mice is sufficient to increase energy expenditure, and enhance thermogenesis in BAT, suggesting that this phenotype is likely centrally regulated, rather than a result of Atf4 deficiency in BAT (28). Indeed, our recently published study demonstrated that deletion of the mitochondrial protein optic atrophy 1 (OPA1) in BAT lead to upregulation of Atf4, which was required for the induction and secretion of FGF21 as a batokine and was associated with improved thermoregulation (9). Moreover, a recent study showed that selective induction of ATF4 in brown adipocytes improves cold tolerance in mice (8).…”

“…Activation of this ATF4-FGF21 axis was required to mediate an adaptive response characterized by elevated resting metabolic rates, and improved thermoregulation in OPA1-deficient mice (9).…”