Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease

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   Figure 1

   Schematic illustration of the lipolytic pathway. To fully hydrolyze TGs, ATGL, HSL, and MGL act in sequence, with the release of one FFA in each step. This successively converts TG to DG, then to MG, and finally to glycerol and a total of tree FFA. TG, triglyceride; ATGL, adipose TG lipase; DG, diacylglycerol; FFA, free fatty acid; HSL, hormone-sensitive lipase; MG, monoacylglycerol; MGL, monoglyceride lipase.
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   Figure 2

   Primary signaling pathways in human lipolysis. Black and red lines indicate pro-lipolytic and anti-lipolytic signaling events, respectively. Arrows indicate stimulation and/or translocation and blunt lines indicate inhibition. Stimulation of lipolysis is dependent on PKA- or PKG-mediated phosphorylation of HSL and PLIN1. PKG is activated by cGMP, which is increased in response to activation of the GC-coupled NPR-A. Similarly, stimulation of the G_s-protein-coupled β_1/2-ARs activates AC, which generates cAMP and activates PKA. Conversely, activation of G_i-protein-coupled α₂-ARs inhibits AC and thereby reduces cAMP-dependent signaling to lipolysis. Stimulation of the insulin signaling pathway through the IR increases the activity of PDE3B, which converts cAMP to 5′-AMP, thus decreasing PKA activity and suppressing lipolysis. PKG activity is reduced by PDE5-mediated conversion of cGMP to 5′-GMP, although the upstream signals regulating this process are currently unknown. The dashed line indicates a putative Akt-independent insulin pathway acting selectively on PLIN1. α₂-ARs, α₂-adrenergic receptors; AC, adenylyl cyclase; TG, triglyceride; ATGL, adipose TG lipase; β_1/2-ARs, β₁- and β₂-adrenergic receptors; CGI-58, comparative gene identification-58; DG, diacylglycerol; FFA, free fatty acid; GC, guanylyl cyclase; HSL, hormone-sensitive lipase; IR, insulin receptor; IRS1/2, IR substrates 1 and 2; MG, monoacylglycerol; MGL, monoglyceride lipase; NPR-A, type-A natriuretic peptide receptor; PDE3B, phosphodiesterase 3B; PDK, phosphoinositide-dependent kinase; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A; PKB/Akt, protein kinase B; PLIN1, perilipin 1.
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   Figure 3

   Alternative signaling pathways in lipolysis. Black and red lines indicate pro-lipolytic and anti-lipolytic signaling events, respectively. Arrows indicate stimulation and blunt lines indicate inhibition. Dashed lines illustrate the indirect lipolytic effects of growth hormone and glucocorticoids by modulation of receptor sensitivities and ANGPTL4-mediated signaling. Although the identity of the ANGPTL4 receptor is unknown, the intracellular signaling has been shown to involve activation of AC. Stimulation of the G_s-protein-coupled melanocortin (MC) receptor and TSH receptor (TSH-r) also increases intracellular cAMP levels through activation of AC. Conversely, the G_i-protein-coupled receptors for NPY/PYY (NPY-Y₁), adenosine (A1-R), β-hydroxybutyrate (HM74a), and lactate (GPR81) suppress lipolysis by inhibition of AC. Pro-inflammatory signaling through the TNF-α receptor (TNFR-1) increases lipolysis by suppressing antilipolytic signaling mediated by the insulin receptor (IR) and α₂-adrenergic receptors (α₂-ARs). For clarity, the intermediate intracellular steps in the different signaling pathways have been omitted. AC, adenylyl cyclase; ANGPTL4, angiopoietin-like protein 4; ATGL, adipose triglyceride lipase; β_1/2-ARs, β₁- and β₂-adrenergic receptors; CGI-58, comparative gene identification-58; DG, diacylglycerol; FFA, free fatty acid; G_i, inhibitory G-protein; G_s, stimulating G-protein; HSL, hormone-sensitive lipase; MG, monoacylglycerol; MGL, monoglyceride lipase; PKA, protein kinase A; PLIN1, perilipin 1; TG, triglyceride; TSH, thyroid-stimulating hormone.
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   Figure 4

   Regulation of ATGL. (A) In the basal state, CGI-58 is complexed with PLIN1 and ATGL activity is low. (B) Upon phosphorylation of PLIN1, CGI-58 is released and associates with ATGL, which increases ATGL activity. In this phase, a fraction of the ATGL pool is dominantly inhibited by G0S2. (C) If the lipolytic stimulation persists, gradual degradation of G0S2 promotes a further increase in ATGL activity. TG, triglyceride; ATGL, adipose TG lipase; CGI-58, comparative gene identification-58; DG, diacylglycerol; G0S2, G₀/G₁ switch gene 2; PKA, protein kinase A; PLIN1, perilipin 1.
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   Figure 5

   Regulation of HSL. (A) Phosphorylation of Ser⁵⁵², Ser⁶⁴⁹, and Ser⁶⁵⁰ on human HSL promotes lipase activation and association with FABP4 in the cytosol. Subsequent translocation of this complex to the LD surface is dependent on both HSL and PLIN1 phosphorylation and results in full activation of HSL activity. Acting as a molecular chaperone, FABP4 shuttles the FFAs released by HSL from the LD to the plasma membrane of the adipocyte where they are secreted. (B) LD-targeting of cytoplasmic HSL requires cAMP-dependent phosphorylation on Ser⁵⁵² by PKA. Conversely, AMPK is activated by 5′-AMP and phosphorylate HSL on the adjacent Ser⁵⁵⁴. As phosphorylation on Ser⁵⁵² and Ser⁵⁵⁴ is mutually exclusive, AMPK reduces the LD association of HSL. AMPK, AMP-activated protein kinase; DG, diacylglycerol; FABP4, fatty acid-binding protein 4; FFA, free fatty acid; HSL, hormone-sensitive lipase; MG, monoacylglycerol; PDE3B, phosphodiesterase 3B; PKA, protein kinase A.

• © 2014 Society for Endocrinology