Tissue-specific mechanisms of fat metabolism that focus on insulin actions

Abstract

Background: The accumulation of ectopic fats is related to metabolic syndromes with insulin resistance, which is considered as the first hit in obesity-related diseases. However, systematic understanding of the occurrence of ectopic fats is limited, since organisms are capable of orchestrating complicated intracellular signaling pathways to ensure that the correct nutritional components reach the tissues where they are needed. Interestingly, tissue-specific mechanisms lead to different consequences of fat metabolism with different insulin sensitivities.

Aim of review: To summarize the mechanisms of fat deposition in different tissues including adipose tissue, subcutis, liver, muscle and intestines, in an attempt to elucidate interactive mechanisms involving insulin actions and establish a potential reference for the rational uptake of fat.

Key scientific concepts of review: Tissue-specific fat metabolism serves as a trigger for developing abnormal fat metabolism or as a compensatory agent for regulating normal fat metabolism. Outcomes of de novo lipogenesis and adipogenesis differ in the subcutaneous adipose tissue (SAT), liver and muscle, with the participation of insulin actions. Overload of lipid metabolic capability results in SAT fat expansion, and ectopic fat accumulation implicates impaired lipo-/adipogenesis in SAT. Regulating insulin actions may be a key measure on fat deposition and metabolism in individuals.

Keywords: Ectopic fat; Fat deposition; Insulin; Metabolism; Obesity.

Graphical abstract

Fig. 1

Fat Deposition in adipose tissue. Classical WNT/β-catenin signaling regulates the growth and differentiation of AMSCs/AMPCs, leading to the acquisition of a white or a brown phenotype. With the help of the BMP family (e.g. BMP4), WAT can transform to beige adipocytes and BAT. Diet-derived fats or carbohydrates contribute to lipogenesis or de novo lipogenesis in adipocytes. Lipolysis from TGs or chylomicrons also supplies fats for lipogenesis. Furthermore, fat lipolysis is an adaptive mechanism in the production of LDL and HDL, and prepares substrates for β-oxidation/thermogenesis in adipocytes (mainly BAT). Lipophagy occurs in states of insufficient nutrients, in which lipid droplets are broken down by the autophagy protein LC3B and its partner lipase ATGL. AMPCs, adipose mesenchymal precursor cells; AMPK, AMP-activated protein kinase; AMSCs, adipose mesenchymal stem cells; ATGL, adipose triglyceride lipase; ATL, adipocyte triglyceride lipase, BAs, bile acids; BAT, brown adipose tissue; BMP, bone morphogenetic protein; cAMP, cyclic-AMP; D2, type 2 iodothyronine deiodinase; FAs, fatty acids; FAHFAs, fatty acid esters of hydroxy fatty acids; HDL, high density lipoprotein; IL-6, interleukin-6; LC3B, light chain-3B; LDL, low density lipoprotein; NFIA, Nuclear factor I-A; PPARγ, peroxisome proliferator-activated receptor γ; RBP4, retinol binding protein-4; TG, triglyceride; TGR5, Takeda G protein-coupled receptor 5; TNF-α, tumor necrosis factor α; UCP-1, uncoupling protein-1; WAT, white adipose tissue; WISP2, WNT1 inducible signaling pathway protein 2; WNT, wingless-type MMTV integration site; ZFP423, zinc-finger protein 423.

Fig. 2

Subcutaneous fat deposition. Diet-derived fats enter SAT with the help of CD36/FATP3, and SAT-secreted angiopoietin-2 contributes to angiogenesis and the activation of CD36/FATP3 by binding with integrin α5β1, which accelerates the transport of FAs. The endothelial Flt1 gene inhibits VEGF-B, and the deletion of the Flt1 gene contributes to VEGFR-2-stimulated angiogenesis. This is followed by enhanced thermogenesis in SAT through UCP-1 and PGC-1α. Both insulin and mTORC2 promote de novo lipogenesis by activating AKT at phosphorylation sites Thr308/309 and Ser473/474, respectively. This drives ChREBPβ to increase de novo lipogenesis in SAT. Furthermore, Gremlin-1 secreted by (pre)adipocytes is an antagonist of BMP4/7, whose production inhibits adipogenesis in WAT with hypertrophic obesity. ACC, acetyl-CoA carboxylase; AKT, serine/threonine protein kinase; ACLY, ATP citrate lyase; BMP, bone morphogenetic protein; FAs, fatty acids; FASN, fatty acid synthase; FATP3, fatty acid transport protein-3; GLUT4, glucose transporter 4; INSR, insulin receptors; mTORC2, mTOR complex 2; PDK1, phosphoinositide dependent kinase-1; PGC-1α, PPARγ coactivator-1α; SAT, subcutaneous adipose tissue; TCA, tricarboxylic acid; UCP-1, uncoupling protein-1; VEGF, vascular endothelial growth factor.

Fig. 3

Fat Deposition in Muscle. Insulin promotes the phosphorylation of RalGAPα1 and breaks down the RalA complex. GTP-loaded RalA promotes the docking and translocation of CD36 and GLUT4, which promote FA and glucose uptake. However, muscle endothelial fat-related genes (e.g. FTO) promote insulin resistance and influence the transport of FAs and glucose. Under condition of low glucose level, NAD⁺ induces the activation of PGC-1α through the SIRT1 signaling pathway. This is followed by the promotion of genes related to TCA, the respiratory chain, and FA utilization, and ultimately promotes the β-oxidation of FAs. CPT1 and AMPK play essential roles in mitochondrial β-oxidation. PHD3 or high-level phosphate inhibits mitochondrial β-oxidation by the hydroxylation of ACC or decreasing physical activity, respectively. Caspase-1-activated IL-18 increases lipolysis in adipose tissue and promotes AMPK-dependent β-oxidation. Moreover, exercise changes the metabolic programs of kynurenine, which leads to peripheral kynurenic acid accumulation to activate GPR35 and increase energy expenditure. ACC2, acetyl-CoA carboxylase 2; AMPK, AMP-activated protein kinase; BAT, brown adipose tissue; CD36, cluster of differentiation 36; CPT1, carnitine palmitoyltransferase-1; cyt c, cytochrome c; FAs, fatty acids; FATPs, fatty acid transport proteins; GLUT4, glucose transporter 4; GPIHBP1, glycosylphosphatidylinositol- anchored high density lipoprotein-binding protein 1, GPR35, G-protein coupled receptor 35; GTP, guanosine triphosphate; IDH3α, isocitrate dehydrogenase alpha subunit; IL-18, interleukin 18; INSR, insulin receptors; LPL, lipoprotein lipase; Myf5, myogenic factor 5; MyoD, myogenic differentiation; PGC-1α, PPARγ coactivator-1α; PHD3, prolyl hydroxylase 3; PPARγ, peroxisome proliferator-activated receptor γ; RalGAP, RalGTPase-activating protein; SIRT1, sirtuin 1;TCA, tricarboxylic acid.

Fig. 4

Fat deposition in the liver. Diet-derived fats, sugars (glucose and fructose), and NEFAs from lipolysis account for 14.9 %, 26.1 %, and 59 % to comprise the TG pool respectively, in the liver. TG is stored as lipid droplets or assembled into VLDL to enter BA circulation. Cholesterol is another form of fat in the liver that maintained in two forms, FC and CE, and a sustainable conversion between these two forms occurs with the help of ACATs and CEH. The intrahepatic circulation of cholesterol relies on CE from the intestinal absorption of FC. Intrahepatic glucagon is decomposed based on ATL, which contributes to the production of acetyl-CoA and FC. The activation of LDLR facilitates the uptake of LDL-c and thus decreases the levels of circulating LDL-c, while LXR-induced transcription of Idol degrades the structure of LDLR. However, miR-148a increases the expression of LDLR, which decreases the circulating LDL-c but increases HDL-c. Activated insulin actions help decrease gluconeogenesis, and PTPN1 gene dephosphorylates INSR to disrupt insulin actions. Moreover, PTPN1 increases the expression of SREB1c and promote lipogenesis in the liver, which can be reversed by miR-206 and FXR-dependent BAs, and TRAF5 inhibits liver lipogenesis by suppressing JNK1. ACATs, acylcoenzyme A:cholesterol acyltransferases; ATL, adipocyte triglyceride lipase; BAs, bile acids; CD36, cluster of differentiation 36; CE, cholesteryl ester; CEH, cholesteryl ester hydrolase; CRR, chylomicron remnant receptor; FAs, fatty acids; FATPs, fatty acid transport proteins; FC, free cholesterol; FXRs, farnesoid X receptors; GLUTs, glucose transporters; HDL-c, high-density lipoprotein cholesterol; INSP3R1, inositol triphosphate receptor 1; INSR, insulin receptors; JNK1, c-Jun N-terminal kinase 1; LDL-c, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; LPL, lipoprotein lipase; LXRs, liver X receptors; miR, micro RNA; NEFAs, non-esterified fatty acids; PTPN1, protein tyrosine phosphatase nonreceptor type 1; SCFAs, short-chain fatty acids; SHP, short heterodimer partner; SREB1c, sterol response element-binding protein 1c; TCA, tricarboxylic acid; TG, triglyceride; TK, triose kinase, TRAF5, TNF Receptor Associated Factor 5; VLDL, very low-density lipoprotein.

Fig. 5

Fat Metabolism in Intestines. Diets-derived FAs can induce more stem-cell-like progenitor cells through PPARδ/WNT/β-catenin signaling cascades, which cause progenitor cells to escape physiological regulation and initiate tumor formation. Fats provide intestinal microbiota with energy for growth to coevolve with the host or mediate an innate immune defense against intestinal microbiota associated digestive diseases (e.g. colitis). Homeostasis of fat metabolic program can be affected by microbiota through NFIL3 or circadian rhythms. Disrupted circadian rhythms or ER stress leads to a series of adaptive changes in a tissue-specific manner. The uptake of diet-derived fats relies on NT-stimulated NTR signaling. Activate AMPK in enteroendocrine cells through GPRC6A can reduce the production of NT and FA uptake in enterocytes. AMPK, AMP-activated protein kinase; CPEB4, cytoplasmic polyadenylation element-binding 4; ER, endoplasmic reticulum; FAs, fatty acids; HFD, high-fat diet; Lgr5 ISCs, leucine-rich-repeat-containing G-protein-coupled receptor 5 intestinal stem cells; NFIL3, nuclear factor interleukin-3; NT, neurotensin; NTR, neurotensin receptor.

Fig. 6

Interactive mechanisms of fat deposition centering on insulin actions. Insulin actions can be activated through AKT activation based on INSR. Communications among the liver, intestines, muscle, subcutis and adipose tissue are dependent on different molecules (e.g. EVs, proteins and lipids), which affect tissue-specific or systemic insulin actions. Intestine ω-3 FAs benefits insulin sensitivity, while HIF-2α may lead to insulin resistance. Hepatic plasma membrane-bound sn-1,2-DAGs or adipocyte-produced DAGs can recruit or activate PKCε, which disrupts the integrity of INSR and leads to insulin resistance. Due to a tissue-specific mechanism, the beneficial effect of de novo lipogenesis in SAT (with increased levels of insulin-sensitizing palmitoleate) are in contrast to the detrimental effect of de novo lipogenesis in the liver (with increased TG level, insulin resistance and metabolic syndromes). Likewise, the beneficial effects of adipogenesis in SAT (with higher lipid buffering capacity) are in contrast to the detrimental effects of adipogenesis in muscle (with more fat infiltrates and muscle steatosis). AKT-2, serine/threonine protein kinase-2; DAGs, diacylglycerols; DES1, dihydroceramide desaturase-1; DPP4, dipeptidyl peptidase 4; Ecscr, endothelial cell surface expressed chemotaxis and apoptosis regulator; EVs, extracellular vesicles; FAHFAs, fatty acid esters of hydroxy fatty acids; FGF21, fibroblast growth factor 21; FoxO1, forkhead box protein O1; GLUT4, glucose transporter 4; GPR120, G protein-coupled receptor 120; GSK3, glycogen synthase kinase-3; HFD, high-fat diet; HIF-2α hypoxia-inducible factor-2α; INSR, insulin receptors; INSR, insulin receptors; INSRS1, insulin receptor substrate 1; NEU3, neuraminidase 3; NLRP3, NOD-like receptor family pyrin domain containing 3; PKCε, protein kinase C-ε; RBP4, retinol binding protein-4; SAT, subcutaneous adipose tissue; S6K1, S6 kinase 1; VDR, vitamin D receptor.

Fig. 7

Insulin actions in regulating fat deposition and metabolism. LXREs, LXR response elements; NF-Y, nuclear factor-Y; SAT, subcutaneous adipose tissue; Sp1, specificity protein 1; SRE, sterol response element; SREBP-1c, sterol-regulatory-element-binding protein-1c.