Mitochondrial Reactive Oxygen Species Control the Transcription Factor CHOP-10/GADD153 and Adipocyte Differentiation

Abstract

Recent reports emphasize the importance of mitochondria in white adipose tissue biology. In addition to their crucial role in energy homeostasis, mitochondria are the main site of reactive oxygen species generation. When moderately produced, they function as physiological signaling molecules. Thus, mitochondrial reactive oxygen species trigger hypoxia-dependent gene expression. Therefore the present study tested the implication of mitochondrial reactive oxygen species in adipocyte differentiation and their putative role in the hypoxiadependent effect on this differentiation. Pharmacological manipulations of mitochondrial reactive oxygen species generation demonstrate a very strong and negative correlation between changes in mitochondrial reactive oxygen species and adipocyte differentiation of 3T3-F442A preadipocytes. Moreover, mitochondrial reactive oxygen species positively and specifically control expression of the adipogenic repressor CHOP-10/ GADD153. Hypoxia (1% O 2 ) strongly increased reactive oxygen species generation, hypoxia-inducible factor-1 and CHOP-10/GADD153 expression, and inhibited adipocyte differentiation. All of these hypoxia-dependent effects were partly prevented by antioxidants. By using hypoxia-inducible factor-1␣ (HIF-1␣)-deficient mouse embryonic fibroblasts, HIF-1␣ was shown not to be required for hypoxia-mediated CHOP-10/GADD153 induction. Moreover, the comparison of hypoxia and CoCl 2 effects on adipocyte differentiation of wild type or HIF-1␣ deficient mouse embryonic fibroblasts suggests the existence of at least two pathways dependent or not on the presence of HIF-1␣. Together, these data demonstrate that mitochondrial reactive oxygen species control CHOP-10/GADD153 expression, are antiadipogenic signaling molecules, and trigger hypoxia-dependent inhibition of adipocyte differentiation.White adipose tissue is the main energy store in adult mammals and displays great plasticity according to the energy needs of the organism. Adipocyte differentiation results from a subtle balance of sequential and interdependent transcription factors expression that activate or inhibit promoters of adipogenic genes.

Lipodystrophy in HIV 1-infected patients: lessons for obesity research

“…37 Finally, ROS are capable of inducing TNFa and interleukin-6 expression in adipocytes, 38 and it has recently been reported that the extent of mitochondrial ROS production by adipocytes is involved in the control of adiponectin release through changes in the levels of CHOP-10, 39 a transcription factor involved in mediating the action of ROS changes in the control of adipocyte differentiation. 33 This is consistent with the low adiponectin levels found in HALS patients 5 and also in some obese patients that are known to contribute to insulin resistance. 40 A summary of Lipodystrophy in HIV 1-infected patients F Villarroya et al the main alterations and potential mechanisms by which mitochondrial disturbances may contribute to HALS is shown in Figure 1.…”

“…However, mitochondria are now recognized as being critical components in the control of multiple key cellular processes, from apoptosis to the production of reactive oxygen species (ROS). For instance, mitochondrial by-products such as ROS impair the extent of adipocyte proliferation and differentiation, 32,33 and a known consequence of impaired mitochondrial bioenergetics, such as that occurring in HALS, is an enhancement in ROS production. Several aspects of mitochondrial dysfunction present in adipose tissue from HALS patients, from abnormal respiratory chain activity due to mtDNA depletion to low levels of UCP2, a mitochondrial uncoupling protein involved in the control of ROS production, 17 may lead to permanent oxidative stress in adipose tissue.…”

Clozapine enhances differentiation of adipocyte progenitor cells

“…They reported that propofol, an anesthetic agent, that inhibits mitochondrial respiration and reduces oxidative stress, significantly increased preadipocyte differentiation by 125710%. Similar to propofol 6 and beside its receptor-mediated effects, clozapine is known to induce mitochondrial superoxide release, previously detected in neutrophils of patients under clozapine treatment, 8 and also seen in clozapinetreated preadipocytes. Additionally, the phenolic moiety of both molecules scavenges radicals.…”

“…Oil red staining of the cells confirmed these results (Figure 1b cells to mature adipocytes. Recently, Carriere et al 6,7 demonstrated that the balance between proliferation and differentiation of adipocyte progenitor cells is regulated by intracellular oxidative stress. They reported that propofol, an anesthetic agent, that inhibits mitochondrial respiration and reduces oxidative stress, significantly increased preadipocyte differentiation by 125710%.…”

“…1,2,4 One of the problems with the proposition concerns the prior probability that it is true. Much of the genome is expressed in the brain, many genes encode synaptic proteins, 5 many synapses utilize glutamate, 6 and most of these contain NMDARs. 7 Thus, the proposition is inherently weak, as any randomly selected group of genes is likely to include a large fraction that converge on synapses, glutamate and NMDARs.…”