GDF15 Is Required for Cold-Induced Thermogenesis and Contributes to Improve Systemic Metabolic Health Following Loss of OPA1 in Brown Adipocytes

Abstract

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.

DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy

“…We next considered whether DELE1 may be responsible for physiologic stress responses downstream of OMA1. We focused on cold stress in the heat-producing BAT, as cold stress has been shown to activate OMA1 and, in separate reports, cold stress has been reported to activate the ISR (Quirós et al , 2012; Jena et al , 2023; Flicker et al , 2019; Levy et al , 2023). Given OMA1 can be activated by mitochondrial uncouplers (Ehses et al , 2009; Head et al , 2009), activation of OMA1 in this setting is likely due to the fatty acid driven uncoupled mitochondrial respiration that produces heat (Nicholls, 2023).…”

Macrophages as a Source and Target of GDF-15

“…This anorexic effect is effectively abolished by blocking with a monoclonal antibody directed against GDF-15 and by GDF-15 or GFRAL knockout (KO) [66,102]. Recent studies have suggested that GDF-15 effect on body weight may be also associated with increased energy expenditure and thermogenesis [104]. Recently, Feng Lu et al found that GDF-15/GFRAL binding is an important determinant of the efficacy of ketogenic diet-induced weight loss.…”