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Review
. 2019 Aug 20;31(6):487-501.
doi: 10.1089/ars.2018.7626. Epub 2018 Nov 1.

Autophagy in Adipose Tissue Physiology and Pathophysiology

Maroua Ferhat  1 , Katsuhiko Funai  1 , Sihem Boudina  1
Affiliations
Review

Autophagy in Adipose Tissue Physiology and Pathophysiology

Maroua Ferhat et al. Antioxid Redox Signal. .

Abstract

Significance: Alterations in adipose tissue function have profound consequences on whole body energy homeostasis because this tissue is central for fat accumulation, energy expenditure, glucose and insulin metabolism, and hormonal regulation. With the obesity reaching epidemic proportions globally, it is important to understand the mechanisms leading to adipose tissue malfunction. Recent Advances: Autophagy has originally been viewed as an adaptive response to cellular stress, but in recent years this process was shown to regulate important cellular processes. In adipose tissue, autophagy is a key regulator of white adipose tissue (WAT) and brown adipose tissue (BAT) adipogenesis, and dysregulated autophagy impairs fat accumulation both in vitro and in vivo. Animal studies have also suggested an important role for autophagy and mitophagy during the transition from beige to white fat. Human studies have provided evidence for altered autophagy in WAT, and these alterations correlated with the degree of insulin resistance. Critical Issues: Despite these important advances in the study of autophagy in adipose tissue, we still do not understand the physiological role of autophagy in mature white and brown adipocytes. Furthermore, several human studies involving autophagy assessment were performed on whole adipose tissue, which complicates the interpretation of the results considering the cellular heterogeneity of this tissue. Future Directions: Future studies will undoubtedly expand our understanding of the role of autophagy in fully differentiated adipocytes, and uncover novel cross-talks between this tissue and other organs in regulating lipid metabolism, redox signaling, energy homeostasis, and insulin sensitivity.

Keywords: adipogenesis; adipose tissue; autophagy; insulin resistance; obesity; thermogenesis.

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Figures

<b>FIG. 1.</b>
FIG. 1.
The autophagic steps in mammalian cells. Autophagy is initiated upon activation of upstream signals, and results in activation of ULK1 and class III PI3KC3. Elongation of the phagophore and maturation of autophagosome requires a conjugation system consisting of ATG3, ATG4, ATG5-ATG12, ATG7, ATG8 (or LC3), ATG10, and ATG16L. Cellular material targeted for degradation is marked by adaptor proteins such as p62 (or sequestosome 1), and then engulfed in autophagosomes. The mature autophagosome then fuses with lysosomes, and the cargo is degraded by lysosomal hydrolases. ATGs, autophagy related genes; ATP, adenosine triphosphate; PI3K3C, phosphatidylinositol-4,5-bisphosphate 3-kinase; ULK1, Unc-51-like kinase 1. Color images are available online.
<b>FIG. 2.</b>
FIG. 2.
The main regulators of autophagy in adipose tissue. Autophagy is regulated both transcriptionally and post-translationally. Nutrient stress such as overfeeding or starvation modulates autophagy through two main arms: mTORC1 activation (overfeeding) and AMPK (starvation). Phosphorylation of ULK1-FIP200-ATG13 complex by mTORC1 leads to its dissociation and inactivation. In contrast, during starvation, AMPK is activated, leading to ULK1/FIP200-ATG13 activation and autophagy initiation. AMPK also phosphorylates the mTORC1 inhibitor TSC2, thus activating autophagy. PKA activates autophagy in beige adipose tissue in response to β-adrenergic stimulation. The effect of PKA on autophagy may involve the transcription factors CREB, Mitf, and FoxO3. Similarly, mTORC1 activation inhibits the nuclear translocation of Tfeb, a transcription factor important for autophagy/lysosomal function. AMPK, adenosine monophosphate-activated protein kinase; CREB, cAMP response element binding; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; PKA, protein kinase A; Tfeb, transcription factor EB; TSC2, tuberous sclerosis 2. Color images are available online.
<b>FIG. 3.</b>
FIG. 3.
The role of autophagy in adipogenesis. Autophagy is upregulated during the conversion of preadipocytes to adipocytes. Deletion of autophagy proteins (Atg5, Atg7, Atg13, ULK2, or beclin) reduced adipogenesis in vitro and in vivo. One of the mechanisms involved in autophagy induction during adipogenesis is the transcriptional induction of Atg4b by C/EBPβ. The induction of Atg4b expression and the ubiquitination of Klf2 and 3 by p62 help eliminate these two negative regulators of adipogenesis. Color images are available online.
<b>FIG. 4.</b>
FIG. 4.
Repression of autophagy/mitophagy is necessary for beige fat maintenance. Upon β-adrenergic stimulation, beige fat is recruited into white adipose tissue through a process that does not require autophagy. Upon removal of the β-adrenergic stimulation, beige fat converts back to white fat through the autophagic/mitophagic clearance of mitochondria. Adenylate cyclase (AC)/cAMP/PKA represses autophagy to maintain beige fat upon β-adrenergic stimulation. In brown fat, some studies showed that the same cAMP/PKA pathway can repress autophagy during β-adrenergic stimulation. ? represents an inhibition that is not yet confirmed. Color images are available online.
<b>FIG. 5.</b>
FIG. 5.
The state of adipose autophagy in obese diabetic humans and animals. The state of autophagy in adipose tissue of obese diabetic humans and animals is controversial. We summarized in this schematic studies showing enhanced or reduced autophagy in obese diabetic adipose tissue of humans and animals (mostly rodents). References are provided in parentheses and are cited in the main text. mRNA, messenger RNA. Color images are available online.
<b>FIG. 6.</b>
FIG. 6.
The role of autophagy in adipocytes–macrophages cross-talk. In physiological conditions, autophagy regulates inflammation, ROS levels, and M1 to M2 shift in macrophages population. During inflammatory conditions, such as diabetes or HFD, autophagy is impaired in macrophages, which impair ROS regulation, cytokine production, and M1/M2 ratio. Concomitantly, increased inflammatory cytokines such as IL1β, IL18, and TNFα produced by M1 macrophages inhibit Akt signaling pathway in adipocytes, resulting in the development of insulin resistance. Leptin produced by adipocytes inhibits autophagy, which impact ER stress response and inflammation in adipocytes. ER, endoplasmic reticulum; HFD, high-fat diet; ROS, reactive oxygen species. Color images are available online.
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