CHOP is dispensable for exercise-induced increases in GDF15

Abstract

Growth differentiating factor-15 (GDF15) is expressed, and secreted, from a wide range of tissues and serves as a marker of cellular stress. A key transcriptional regulator of this hormone is the endoplasmic reticulum stress protein, CHOP (C/EBP Homologous Protein). Exercise increases GDF15 levels but the underlying mechanisms of this are not known. To test whether CHOP regulates GDF15 during exercise we used various models of altered ER stress. We examined the effects of acute exercise on circulating GDF15 and GDF15 mRNA expression in liver, triceps skeletal muscle, and epididymal white adipose tissue and examined the GDF15 response to acute exercise in lean and high-fat diet-induced obese mice, sedentary and exercise trained mice, and CHOP deficient mice. We found that obesity augments exercise-induced circulating GDF15 although ER stress markers were similar in lean and obese mice. Exercise-induced GDF15 was increased in trained and sedentary mice that ran at the same relative exercise intensity, despite trained mice being protected against increased markers of ER stress. Finally, exercise-induced increases in GDF15 at the tissue and whole-body level were intact in CHOP deficient mice. Together, these results provide evidence that exercise-induced GDF15 expression and secretion occurs independent of ER stress/CHOP.

GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion

“…It is also known that muscle contraction upregulates synthesis, posttranslational modification, and signaling of membrane trafficking proteins ( 65 ). However, it was recently demonstrated that CHOP was not required for contraction-induced GDF15 release ( 66 ), whereas it was shown that AMPK is a central mediator when energy deficiency is present in the liver ( 67 ). Given that exercise activates AMPK signaling in skeletal muscle, there is the possibility that contraction-stimulated AMPK activation is a GDF15-driven mechanism in muscle.…”

Mitochondrial Stress Links Environmental Triggers with Pro-Inflammatory Signaling in Crohn’s Disease

“…Furthermore, although our study was not designed to assess the role of each transcription factor on target genes, our correlation analysis may suggest that the expression of GDF15 is not CHOP-dependant but rather ATF4-and ATF5-dependant. In fact, a previous study found that CHOP is dispensable for exercise-induced expression of GDF15 [29]. Furthermore, levels of TRAP1 decrease after treatment with ibuprofen.…”

“…However, increased levels of GDF15 are found not only in primary mitochondrial disorders [24] but also in different diseases like neurodegenerative diseases [25], cardiovascular diseases [26], and cancer [27]. Furthermore, GDF15 is elevated in conditions like aging [28] or exercise [29]. GDF15 has been previously related to CD.…”

Dietary medium-chain fatty acids reduce food intake via the GDF15-GFRAL axis in mice

“…The mechanism behind the MCFA-induced increase in Gdf1 5 mRNA is not yet understood. Intake of MCFAs did not increase mRNA levels of Atf4 and Chop , suggesting that the integrated stress response pathway is not involved in the induction of GDF15, as was also observed in other physiological stimuli such as exercise [ 51 ]. Interestingly, it has been shown that activation of the cellular stress sensor, AMPK, can increase hepatic GDF15 levels [ 52 ].…”