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, that is activated independently of BAT thermogenic function.

Previously we showed that mice lacking the protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) have induction of the activating transcription factor 4 (ATF4), which promotes fibroblast growth factor 21 (FGF21) secretion as a batokine. FGF21 increases metabolic rates at baseline conditions but is dispensable for the resistance to diet-induced obesity (DIO) reported in OPA1 BKO mice [1]. To determine alternative mediators of this phenotype, we performed transcriptome analysis, which revealed increased levels of growth differentiation factor 15 (GDF15) in BAT. To determine if ATF4 induction was mediated by the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and to evaluate the contribution of GDF15 to the resistance to DIO, we selectively deleted PERK or GDF15 in OPA1 BKO mice. Mice lacking both OPA1 and PERK in BAT had preserved induction of ATF4. Importantly, simultaneous deletion of OPA1 and GDF15 partially reversed the resistance to diet-induced obesity and abrogated the improvements in glucose tolerance. Furthermore, GDF15 mediated cold-induced thermogenesis, likely via sympathetic activation of iWAT. Taken together, our data indicate that PERK is dispensable for ATF4 induction, but GDF15 contributes to the resistance to DIO, and is required for glucose homeostasis and thermoregulation in OPA1 BKO mice.

Brown and beige adipocytes dissipate chemical energy as heat through thermogenic respiration, thereby playing important roles in adaptive thermogenesis and energy homeostasis in mice. The Protein Kinase R (PKR)-Like Endoplasmic Reticulum Kinase (PERK) has been shown to be required for mitochondrial thermogenesis in cultured brown adipocytes, and in mice lacking PERK in white and brown adipose tissues. Here, we tested the hypothesis that PERK expression specifically in thermogenic adipocytes is required for adaptive thermogenesis and to regulate energy homeostasis in mice, by selectively deleting PERK in Ucp1-expressing cells (brown and beige adipocytes) of male and female mice. At baseline conditions, mitochondria oxygen consumption rates (OCR) were significantly reduced in brown adipocytes isolated from male, but not from female KO mice. After being housed at thermoneutrality for 7 days (30 °C), wild type (WT) and KO mice were exposed to 4 °C for 3 days. Surprisingly, both male and female KO mice were able to properly adapt to cold exposure, as demonstrated by preserved core body temperatures relative to WT mice. Interestingly, age-induced weight gain, fat mass expansion and impairments in glucose homeostasis were all attenuated in KO males, while weight gain was exacerbated in KO females. This correlated with increased energy expenditure (EE) in male mice, while EE was reduced in female mice. We, next, tested the hypothesis that male KO mice would be resistant to diet-induced obesity. After 12 weeks of high-fat feeding (60% calories from fat), male KO mice became as obese, glucose intolerant and insulin resistant as WT mice. In conclusion, our data suggest that PERK expression in thermogenic adipocytes reduces mitochondrial OCR in male mice, but is dispensable for thermoregulation after short-term cold exposure in both male and female mice. Furthermore, our data reveal a sex-dependent effect of PERK in thermogenic adipocytes in the regulation of energy homeostasis, which is dependent on changes in EE. Disclosure J.Jena: None. L.M.García-peña: None. R.Pereira: None. Funding National Institutes of Health (DK125405, 2T32DK112751-06)