..defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity.., 2020, Choi et al

[Andy]

Full title - An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models

Aims/hypothesis
Mitochondrial oxidative phosphorylation (OxPhos) is essential for energy production and survival. However, the tissue-specific and systemic metabolic effects of OxPhos function in adipocytes remain incompletely understood.

Methods
We used adipocyte-specific Crif1 (also known as Gadd45gip1) knockout (AdKO) mice with decreased adipocyte OxPhos function. AdKO mice fed a normal chow or high-fat diet were evaluated for glucose homeostasis, weight gain and energy expenditure (EE). RNA sequencing of adipose tissues was used to identify the key mitokines affected in AdKO mice, which included fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). For in vitro analysis, doxycycline was used to pharmacologically decrease OxPhos in 3T3L1 adipocytes. To identify the effects of GDF15 and FGF21 on the metabolic phenotype of AdKO mice, we generated AdKO mice with global Gdf15 knockout (AdGKO) or global Fgf21 knockout (AdFKO).

Results
Under high-fat diet conditions, AdKO mice were resistant to weight gain and exhibited higher EE and improved glucose tolerance. In vitro pharmacological and in vivo genetic inhibition of OxPhos in adipocytes significantly upregulated mitochondrial unfolded protein response-related genes and secretion of mitokines such as GDF15 and FGF21. We evaluated the metabolic phenotypes of AdGKO and AdFKO mice, revealing that GDF15 and FGF21 differentially regulated energy homeostasis in AdKO mice. Both mitokines had beneficial effects on obesity and insulin resistance in the context of decreased adipocyte OxPhos, but only GDF15 regulated EE in AdKO mice.

Conclusions/interpretation
The present study demonstrated that the adipose tissue adaptive mitochondrial stress response affected systemic energy homeostasis via cell-autonomous and non-cell-autonomous pathways. We identified novel roles for adipose OxPhos and adipo-mitokines in the regulation of systemic glucose homeostasis and EE, which facilitated adaptation of an organism to local mitochondrial stress.

Paywall, https://link.springer.com/article/10.1007/s00125-019-05082-7
Sci hub, https://sci-hub.se/10.1007/s00125-019-05082-7

 

[Hutan]

Thinking aloud here, do join in/correct me if you feel like it.

Mitochondrial oxidative phosphorylation (Oxphos) is the production of ATP in mitochondria; it uses oxygen. (Whereas glycolysis happens in the cytoplasm (in the cell but outside the mitochondria) and doesn't use oxygen).

So these researchers have gene knock-out mice that have reduced Oxphos in their adipocytes (adipocytes = essentially, fat cells). And that's interesting because people with ME seem to have reduced Oxphos, especially when in PEM. I think we swap to glycolysis quicker than healthy people during a CPET (and quicker again in another CPET the following day).

Mitochondrial OxPhos deficits cause proteotoxic stress, which initiates the UPRmt (mitochondrial unfolded protein response) to induce mitochondrial proteostasis, a highly conserved mitoprotective mechanism

They also did an in vitro analysis -

doxycycline was used to pharmacologically decrease OxPhos in 3T3L1 adipocytes

So doxycycline decreased OxPhos in fat cells! and also initiates the mitochondrial unfolded protein response. Maybe it does that in other cells too? (I wonder, could extended courses of doxycycline for malaria prophylaxis be harmful in some people?)

Adipocyte-specific impairment of OxPhos function is associ- ated with greater synthesis of adipo-mitokines in vivo

expression of major mitokines, such as Gdf15 and Fgf21, was much higher in the adipose tissue of AdKO mice compared with control mice (Fig. 6a and ESM Fig. 9b), as was the expression of metabolic pathway genes and genes involved in the phosphoinositol 3-kinase (PI3)–Akt and peroxisome proliferator-activated receptor signalling pathways

That's interesting because Nacul et al found

Accounting for potential confounders, severely affected ME/CFS patients had GDF15 concentrations that were significantly increased compared to healthy controls (P = 0.01). GDF15 levels were positively correlated (P = 0.026) with fatigue scores in ME/CFS.

(although there was speculation that the GDF15 was inversely related to activity levels).

Although there is presently no evidence for a role of the UPRmt in longevity or metabolic diseases in mammals, mitokines such as FGF21 and GDF15 are not only useful diagnostic biomarkers for human mitochondrial diseases, but are also a potential therapeutic modality for metabolic diseases [18, 35, 36, 38, 39]. Moreover, Fgf21−/− and Gdf15−/− mice [i.e. mice that can't make FGF21 or GDF15] are prone to HFD [High Fat Diet] -induced obesity, glucose intolerance, and hepatic and adipose inflammation [40, 41], suggesting an important role for these mitokines in whole-body metabolic homeostasis.

 

[Hutan]

Another paper
Mitochondrial proteostasis in the context of cellular and organismal health and aging

Specifically, a block in mitophagy in muscle cells caused these cells to secrete an FGF21 mitokine into the serum (145). Follow-up in C2C12 cells showed that FGF21 expression is induced as part of an ATF4-dependent integrated stress response, as the FGF21 promoter contains ATF4-binding sites (120). Independently, a GDF15 mitokine was shown to be released from muscle cells upon perturbation of mitochondrial translation or mutation of POLG, and it was confirmed in a muscle cell culture model that GDF15 is up-regulated in a CHOP-dependent but ATF4-independent manner (146). It was recently reported that patients with mtDNA mutations that cause mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) exhibit abnormally high levels of GDF15, which the authors suggest could be used as a biomarker for mitochondrial disease (147).

 

[SNT Gatchaman]

GDF15 and FGF21 are often discussed together in the context of metabolic disorders. FGF21 was found to be elevated in ME in Are Circulating FGF21 and NT-proBNP promising novel biomarkers in ME/CFS (2020).

See also —

• Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response (2021, Cell iScience)
• Circulating FGF21 and GDF15 as Biomarkers for Screening, Diagnosis, and Severity Assessment of Primary Mitochondrial Disorders in Children (2022, Frontiers in Pediatrics)