Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Jul 14;36(14):1999-2017.
doi: 10.15252/embj.201696206. Epub 2017 Jun 16.

Adipose tissue: between the extremes

Alexandros Vegiopoulos  1 , Maria Rohm  2 , Stephan Herzig  3
Affiliations
Review

Adipose tissue: between the extremes

Alexandros Vegiopoulos et al. EMBO J. .

Abstract

Adipose tissue represents a critical component in healthy energy homeostasis. It fulfills important roles in whole-body lipid handling, serves as the body's major energy storage compartment and insulation barrier, and secretes numerous endocrine mediators such as adipokines or lipokines. As a consequence, dysfunction of these processes in adipose tissue compartments is tightly linked to severe metabolic disorders, including obesity, metabolic syndrome, lipodystrophy, and cachexia. While numerous studies have addressed causes and consequences of obesity-related adipose tissue hypertrophy and hyperplasia for health, critical pathways and mechanisms in (involuntary) adipose tissue loss as well as its systemic metabolic consequences are far less understood. In this review, we discuss the current understanding of conditions of adipose tissue wasting and review microenvironmental determinants of adipocyte (dys)function in related pathophysiologies.

Keywords: adipose tissue dysfunction; cachexia; lipodystrophy; metabolic disorders; obesity.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Lipid storage and metabolism in healthy and dysfunctional adipocytes
(A) Functional adipocytes metabolize and store excess circulating lipids and glucose in the inert form of triglycerides in the lipid droplet. Fatty acids can be mobilized by lipolysis on demand. Pancreatic insulin promotes de novo lipogenesis as well as the uptake and storage of circulating lipids. The secretion of adipokines and lipokines by functional adipocytes contributes to systemic metabolic regulation. (B) Impairment of triglyceride storage in overloaded or dysfunctional adipocytes is associated with constitutive fatty acid mobilization, reduced glucose uptake and de novo lipogenesis as well as the generation of lipotoxic diacylglycerol and ceramides (these intermediates also accumulate in remote tissues). These metabolic changes are partly due to insulin resistance (see also Fig 4). Dysfunctional adipocytes are characterized by reduced production of certain lipokines as well as an adverse adipokine profile. Overall, the increased flux of fatty acids away from adipocytes promotes systemic metabolic dysfunction. Adaptive and pathogenic effects are shown in green and red, respectively. MGL, monoglyceride lipase; HSL, hormone‐sensitive lipase; ATGL, adipose triglyceride lipase; ACC, acetyl‐CoA carboxylase.
Figure 2
Figure 2. Obesity and wasting diseases in light of the adipose tissue expandability hypothesis
Both obesity and wasting diseases cause adipose tissue dysfunction due to insufficient storage capacity, resulting in dyslipidemia, systemic inflammation and altered adipokine profiles. Combination of these factors favors the development of insulin resistance and the metabolic syndrome, which further impairs adipose tissue function, creating a futile cycle. IKKβ, IκB kinase; HIF, hypoxia‐inducible factor; IL‐6, interleukin‐6; JNK, c‐Jun N‐terminal kinase; TNF‐α, tumor necrosis factor‐alpha; CRP, C‐reactive protein; DAG, diacylglycerol.
Figure 3
Figure 3. Activation of energy wasting pathways in cancer cachexia
AMPK (adenosine monophosphate‐activated protein kinase) in adipose tissue phosphorylates HSL (hormone‐sensitive lipase) and ACC (acetyl‐CoA carboxylase) at inhibitory sites, blocking lipolysis and lipogenesis. Cachexia‐inducing tumors activate adipocyte lipolysis and lipogenesis by (i) upregulating lipase levels (ATGL, HSL), and (ii) reducing the inhibitory AMPK activity. Cachexia causes reduced AMPK activity due to increased levels and binding to CIDEA (cell death‐inducing DNA fragmentation factor‐alpha‐like effector A) resulting in AMPK complex dissociation. Treatments _targeting adipose tissue AMPK function (including ACIP, AMPK‐CIDEA interfering peptide) have proven beneficial in counteracting cachexia. ZAG, zinc‐alpha2‐glycoprotein; PTHrP, parathyroid hormone‐related protein; NEFA, non‐esterified fatty acid.
Figure 4
Figure 4. Futile cycles driving impaired triglyceride storage and lipolysis
Adipocyte overloading in the absence of compensatory adipocyte formation and angiogenesis or lipodystrophy‐associated impaired triglyceride storage can increase “reactive” lipid intermediates, other cell stressors, and hypoxia and thereby promote inflammation, fibrosis and insulin resistance. These factors interact and synergistically feed back to deteriorate adipocyte metabolism and safe lipid storage. ECM, extracellular matrix; ER, endoplasmic reticulum; HIF1α, hypoxia‐inducible factor 1α; PKC, protein kinase C; ROS, reactive oxygen species; TLR4, Toll‐like receptor 4.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abdennour M, Reggio S, Le Naour G, Liu Y, Poitou C, Aron‐Wisnewsky J, Charlotte F, Bouillot JL, Torcivia A, Sasso M, Miette V, Zucker JD, Bedossa P, Tordjman J, Clement K (2014) Association of adipose tissue and liver fibrosis with tissue stiffness in morbid obesity: links with diabetes and BMI loss after gastric bypass. J Clin Endocrinol Metab 99: 898–907 - PubMed
    1. Abdullahi A, Chen P, Stanojcic M, Sadri7 AR , Coburn N, Jeschke MG (2017) IL‐6 signal from the bone marrow is required for the browning of white adipose tissue post burn injury. Shock 47: 33–39 - PMC - PubMed
    1. Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E, Minnemann T, Shulman GI, Kahn BB (2001) Adipose‐selective _targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409: 729–733 - PubMed
    1. Abreu‐Vieira G, Fischer AW, Mattsson C, de Jong JM, Shabalina IG, Ryden M, Laurencikiene J, Arner P, Cannon B, Nedergaard J, Petrovic N (2015) Cidea improves the metabolic profile through expansion of adipose tissue. Nat Commun 6: 7433 - PubMed
    1. Acharyya S, Ladner KJ, Nelsen LL, Damrauer J, Reiser PJ, Swoap S, Guttridge DC (2004) Cancer cachexia is regulated by selective _targeting of skeletal muscle gene products. J Clin Invest 114: 370–378 - PMC - PubMed

Publication types

  NODES
Association 1
Idea 3
idea 3
twitter 2