OPA1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via FGF21
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Curated by eLife
Evaluation Summary:
The new work utilizes several elegant genetic mouse models to evaluate the importance of the mitochondrial fusion protein OPA1 in thermogenic brown adipocytes. This well-written and rigorous study sheds insight into the importance of OPA1 in brown adipocytes and also uncovers an unexpected compensatory mechanism that ensures thermoregulation in mice.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. 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 by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, which is activated independently of BAT thermogenic function.
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Reviewer #3 (Public Review):
This manuscript is well written and presents several new mouse models including animals with brown fat specific deletion of multiple genes of interest to assess whether they may function in a common pathway. The authors draw on their existing expertise in mitochondrial biology to provide new information regarding the role of OPA1 and mitochondrial dynamics in brown fat function. Weaknesses of this study include a relative lack of mechanistic insights and incomplete characterization of whole-body energy expenditure data from the multiple models reported here.
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Reviewer #2 (Public Review):
Understanding the mechanisms by which thermogenic brown adipocytes become activated in response to adrenergic signaling remains a high priority for the field of adipose tissue biology. The authors of this study investigate the importance of mitochondrial fusion protein optic atrophy 1 (OPA1) in brown adipocytes, which is highly regulated at the transcriptional and post-transcriptional level upon cold exposure and obesogenic conditions. Using a genetic loss of function mouse model, the authors demonstrate BAT specific knockout of OPA1 results in brown adipocyte mitochondrial dysfunction; however, knockout animals have improved thermoregulations due to the activation of compensatory mechanisms. Part of this compensatory mechanism involves the activation of an ATF4 mediated stress response leading to the …
Reviewer #2 (Public Review):
Understanding the mechanisms by which thermogenic brown adipocytes become activated in response to adrenergic signaling remains a high priority for the field of adipose tissue biology. The authors of this study investigate the importance of mitochondrial fusion protein optic atrophy 1 (OPA1) in brown adipocytes, which is highly regulated at the transcriptional and post-transcriptional level upon cold exposure and obesogenic conditions. Using a genetic loss of function mouse model, the authors demonstrate BAT specific knockout of OPA1 results in brown adipocyte mitochondrial dysfunction; however, knockout animals have improved thermoregulations due to the activation of compensatory mechanisms. Part of this compensatory mechanism involves the activation of an ATF4 mediated stress response leading to the induction of FGF21 from brown adipose tissue. These data highlight the presence of homeostatic mechanisms that can ensure thermoregulation in mammals.
Overall, the manuscript is very well-written and the data is nicely presented. The use of multiple genetic mouse models is elegant, rigorous, and yields convincing results. The authors acknowledge the strengths and limitations of the work in a nicely written discussion. This should be a valuable addition to the field, including those interested in mitochondrial biology, brown adipose tissue biology, and FGF21 function. There are minor issues that require attention and one important issue regarding the variability in FGF21 levels observed in the knockout model.
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Evaluation Summary:
The new work utilizes several elegant genetic mouse models to evaluate the importance of the mitochondrial fusion protein OPA1 in thermogenic brown adipocytes. This well-written and rigorous study sheds insight into the importance of OPA1 in brown adipocytes and also uncovers an unexpected compensatory mechanism that ensures thermoregulation in mice.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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