Regulation of diurnal energy balance by mitokines

Abstract

The mammalian system of energy balance regulation is intrinsically rhythmic with diurnal oscillations of behavioral and metabolic traits according to the 24 h day/night cycle, driven by cellular circadian clocks and synchronized by environmental or internal cues such as metabolites and hormones associated with feeding rhythms. Mitochondria are crucial organelles for cellular energy generation and their biology is largely under the control of the circadian system. Whether mitochondrial status might also feed-back on the circadian system, possibly via mitokines that are induced by mitochondrial stress as endocrine-acting molecules, remains poorly understood. Here, we describe our current understanding of the diurnal regulation of systemic energy balance, with focus on fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), two well-known endocrine-acting metabolic mediators. FGF21 shows a diurnal oscillation and directly affects the output of the brain master clock. Moreover, recent data demonstrated that mitochondrial stress-induced GDF15 promotes a day-time restricted anorexia and systemic metabolic remodeling as shown in UCP1-transgenic mice, where both FGF21 and GDF15 are induced as myomitokines. In this mouse model of slightly uncoupled skeletal muscle mitochondria GDF15 proved responsible for an increased metabolic flexibility and a number of beneficial metabolic adaptations. However, the molecular mechanisms underlying energy balance regulation by mitokines are just starting to emerge, and more data on diurnal patterns in mouse and man are required. This will open new perspectives into the diurnal nature of mitokines and action both in health and disease.

Multi-Omics Reveal the Immunological Role and the Theragnostic Value of miR-216a/GDF15 Axis in Human Colon Adenocarcinoma

“…Growth differentiation factor 15 (GDF15) is a well-known endocrine-acting mitokine, which is induced and secreted in response to mitochondrial stress [4]. GDF15 belongs to the transforming growth factor β (TGF-β) superfamily and thus presents the characteristic structure of the TGF-β superfamily [5,6].…”

The Role of GDF15 as a Myomitokine

“…This broader definition was first applied to fibroblast growth factor 21 (FGF21), which was found to be induced in mouse models of autophagy deficiency by targeted disruption of Atg7 (autophagy-related 7) in skeletal muscles or the liver, leading to a protection from obesity and insulin resistance of these mice [ 13 ]. More recently, GDF15 has come into the focus as an additional mitokine, and today FGF21 and GDF15 are considered as two important, endocrine-acting mitokines that are able to initiate systemic adaptations affecting overall energy and substrate metabolism [ 3 , 8 , 14 ].…”

“…Cellular stress such as mitochondrial stress activates the integrated stress response (ISR), a common adaptive pathway for the restoration of cellular homeostasis. Activation of the ISR converges on the increased translation of proteins implicated in stress recovery, such as ATF4, the main regulator of the mitochondrial stress response in mammals, which is crucial for triggering the expression of the two mitokines FGF21 and GDF15 [ 14 ]. Indeed, GDF15 can be considered as an endocrine signal of the ISR, and CHOP was demonstrated as the terminal effector for inducing GDF15 gene expression in response to activation of the ISR [ 4 , 31 , 32 ].…”

Emerging roles of growth differentiation factor‑15 in brain disorders (Review)

“…In 2017, research successively identified glial cell-derived neurotrophic factor receptor α-like (GFRAL) as the receptor of GDF15 (13)(14)(15)(16). Discovery of the GDF15/GFRAL signaling pathway provided a potentially novel target for the treatment of obesity and metabolic diseases (16)(17)(18). In recent years, accumulating evidence has also indicated that GDF15 is associated with a range of brain disorders, including Alzheimer's disease (AD), cerebral stroke and Parkinson's disease (PD) (19)(20)(21).…”