Endocrinol Metab.  2021 Feb;36(1):1-11. 10.3803/EnM.2021.956.

Cellular and Intercellular Homeostasis in Adipose Tissue with Mitochondria-Specific Stress

• Choi MJ
• Jung SB
• Chang JY
• Shong M

• KMID: 2513282
• DOI: http://doi.org/10.3803/EnM.2021.956

Abstract

Paracrine interactions are imperative for the maintenance of adipose tissue intercellular homeostasis, and intracellular organelle dysfunction results in local and systemic alterations in metabolic homeostasis. It is currently accepted that mitochondrial proteotoxic stress activates the mitochondrial unfolded protein response (UPR^mt) in vitro and in vivo. The induction of mitochondrial chaperones and proteases during the UPR^mt is a key cell-autonomous mechanism of mitochondrial quality control. The UPR^mt also affects systemic metabolism through the secretion of cell non-autonomous peptides and cytokines (hereafter, metabokines). Mitochondrial function in adipose tissue plays a pivotal role in whole-body metabolism and human diseases. Despite continuing interest in the role of the UPR^mt and quality control pathways of mitochondria in energy metabolism, studies on the roles of the UPR^mt and metabokines in white adipose tissue are relatively sparse. Here, we describe the role of the UPR^mt in adipose tissue, including adipocytes and resident macrophages, and the interactive roles of cell non-autonomous metabokines, particularly growth differentiation factor 15, in local adipose cellular homeostasis and systemic energy metabolism.

Keyword

Adipocytes; Mitochondria; Macrophages; Energy metabolism; Unfolded protein response

Figure

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  Fig. 1 Impaired mitoribosomal function in adipocytes is linked to increased energy expenditure and protection against diet-induced obesity and associated with the metabokine growth differentiation factor 15 (GDF15). Adipocyte-specific mitoribosomal defect mice (AdKO), caused by Crif1 deficiency, showed altered mitochondrial matrix proteostasis, which resulted in increased levels of chaperones and proteases. AdKO mice showed weight loss and were protected from obesity and insulin resistance. This phenomenon was attributed to increased GDF15 levels in serum and adipose tissue. Thus, GDF15 controlled energy homeostasis and protected from diet-induced obesity in AdKO mice. UPRmt, mitochondrial unfolded protein response.

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  Fig. 2 Impaired mitochondrial oxidative function in adipose tissue macrophages resulting in adipose tissue inflammation and insulin resistance. Mice with a myeloid-specific mitoribosomal defect (MacHO) caused by Crif1 deficiency have higher M1 macrophage populations in adipose tissue. This leads to adipose inflammation and insulin resistance in high fat diet-fed mice. The macrophages from MacHO mice showed low growth differentiation factor 15 (GDF15) responses to a peroxisome proliferator-activated receptor gamma (PPARγ) agonist and T-helper 2 cytokines. Administration of GDF15 in ob/ob and MacHO mice reversed insulin resistance and inflammation, suggesting that GDF15 has an important role in improving the oxidative function of macrophages. WAT, white adipose tissue.

• 

  Fig. 3 Lessons from mitochondrial proteostasis in adipose tissue. Growth differentiation factor 15 (GDF15) is induced by cellular stress, including aging, inflammation, cancer, as well as mitochondrial dysfunction. Adipocyte mitoribosomal stress perturbs mitochondrial proteostasis, which upregulates the metabokine GDF15. GDF15 regulates macrophage polarization toward the M2-like state. M2-like macrophages are also induced by the Th2 cytokines, interleukin 4 (IL-4) and IL-13, which signal through the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) pathway and lead to improvement of glucose homeostasis and insulin sensitivity. GDF15-deficient macrophages are prone to a M1-like phenotype, which is associated with adipose inflammation and systemic insulin resistance. Therefore, GDF15 has a beneficial effect on regulating macrophage polarization in adipose tissue, which is further associated with improvement of systemic metabolism. ATF, activating transcription factor; UPRmt, mitochondrial unfolded protein response.

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  Fig. 4 Mitoribosomal stress couples the mitochondrial unfolded protein response (UPRmt) to systemic energy metabolism. Upregulation of the UPRmt leads to cellular homeostasis with increased mitochondrial proteostasis, known as mitochondrial quality control. The UPRmt also induces growth differentiation factor 15 (GDF15), which binds to GDNF family receptor alpha like (GFRAL) in the area postrema (AP) and the nucleus tractus solitarius (NTS) region of the hindbrain. The GDF15-GFRAL axis acts as a regulator of the anorexigenic effect, resulting in the reduction of body weight. The peripheral action of GDF15 has been demonstrated in various studies, but its receptor in peripheral tissue has not yet been discovered. Therefore, further research is needed to confirm the mechanism of peripheral GDF15 action. PVH, paraventricular nucleus of the hypothalamus.

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