Adipose tissue: between the extremes

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.

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. 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. 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. 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.