Adipose Tissue-Liver Cross Talk in the Control of Whole-Body Metabolism: Implications in Nonalcoholic Fatty Liver Disease

Adipose tissue and the liver play significant roles in the regulation of whole-body energy homeostasis, but they have not evolved to cope with the continuous, chronic, nutrient surplus seen in obesity. In this review, we detail how prolonged metabolic stress leads to adipose tissue dysfunction, inflammation, and adipokine release that results in increased lipid flux to the liver. Overall, the upshot of hepatic fat accumulation alongside an insulin-resistant state is that hepatic lipid enzymatic pathways are modulated and overwhelmed, resulting in the selective buildup of toxic lipid species, which worsens the pro-inflammatory and pro-fibrotic shift observed in nonalcoholic steatohepatitis. Adipose tissue and the liver play significant roles in the regulation of whole-body energy homeostasis, but they have not evolved to cope with the continuous, chronic, nutrient surplus seen in obesity. In this review, we detail how prolonged metabolic stress leads to adipose tissue dysfunction, inflammation, and adipokine release that results in increased lipid flux to the liver. Overall, the upshot of hepatic fat accumulation alongside an insulin-resistant state is that hepatic lipid enzymatic pathways are modulated and overwhelmed, resulting in the selective buildup of toxic lipid species, which worsens the pro-inflammatory and pro-fibrotic shift observed in nonalcoholic steatohepatitis. Michele VaccaView Large Image Figure ViewerDownload Hi-res image Download (PPT)Samuel VirtueView Large Image Figure ViewerDownload Hi-res image Download (PPT)Michael E. D. AllisonView Large Image Figure ViewerDownload Hi-res image Download (PPT)Antonio Vidal-PuigView Large Image Figure ViewerDownload Hi-res image Download (PPT) Obesity develops as a result of a positive chronic energy balance, defined as when caloric intake exceeds energy expenditure. It is emerging as one of the major factors limiting life expectancy in developed countries, and is linked to an increased risk of metabolic syndrome featuring insulin resistance (IR) and type 2 diabetes mellitus, mixed dyslipidemia, and hypertension. Common complications include nonalcoholic fatty liver disease (NAFLD),1Younossi Z. Anstee Q.M. Marietti M. et al.Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat Rev Gastroenterol Hepatol. 2018; 15: 11-20Crossref PubMed Scopus (531) Google Scholar atherosclerosis,2Parhofer K.G. Interaction between glucose and lipid metabolism: more than diabetic dyslipidemia.Diabetes Metab J. 2015; 39: 353-362Crossref PubMed Scopus (96) Google Scholar and cancer.3Flegal K.M. Kit B.K. Orpana H. et al.Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.JAMA. 2013; 309: 71-82Crossref PubMed Scopus (1851) Google Scholar Metabolic syndrome is linked to an underlying impairment of glucose and lipid metabolism in various organs, including adipose tissue (AT) and the liver,4Scherer P.E. Adipose tissue: from lipid storage compartment to endocrine organ.Diabetes. 2006; 55: 1537-1545Crossref PubMed Scopus (683) Google Scholar,5Rui L. Energy metabolism in the liver.Compr Physiol. 2014; 4: 177-197Crossref PubMed Scopus (526) Google Scholar neither of which have evolved to cope with the continuous chronic nutrient surplus seen in obese states. In this review, we consider how AT–liver cross talk goes awry during prolonged metabolic stress, focusing on lipid fluxes, peripheral IR, inflammation, and hormonal signals. We will also discuss how dysregulation of these systems leads to fat accumulation within the liver. The NAFLD spectrum includes histologic features ranging from simple steatosis (NAFL) to steatohepatitis (nonalcoholic steatohepatitis [NASH]) and fibrosis ultimately leading to cirrhosis. Steatosis can be defined histologically (presence of lipid micro- or macrovesicles in >5% of hepatocytes),6Brunt E.M. Janney C.G. Di Bisceglie A.M. et al.Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.Am J Gastroenterol. 1999; 94: 2467-2474Crossref PubMed Scopus (2630) Google Scholar chemically (intrahepatic triglyceride [TG] content >55 mg/g of tissue),7Kwiterovich Jr., P.O. Sloan H.R. Fredrickson D.S. Glycolipids and other lipid constituents of normal human liver.J Lipid Res. 1970; 11: 322-330Abstract Full Text PDF PubMed Google Scholar or by imaging (eg, >5% of liver fat fraction by magnetic resonance).8Szczepaniak L.S. Nurenberg P. Leonard D. et al.Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population.Am J Physiol Endocrinol Metab. 2005; 288: E462-E468Crossref PubMed Scopus (1027) Google Scholar NAFL progresses to NASH when hepatocyte injury, inflammatory infiltrates, and/or extracellular matrix deposition in the form of fibrosis develop.9Michelotti G.A. Machado M.V. Diehl A.M. NAFLD, NASH and liver cancer.Nat Rev Gastroenterol Hepatol. 2013; 10: 656-665Crossref PubMed Scopus (459) Google Scholar NASH places patients at risk of progression to cirrhosis and hepatocellular carcinoma, with consequent liver-related mortality or the need for liver transplantation.9Michelotti G.A. Machado M.V. Diehl A.M. NAFLD, NASH and liver cancer.Nat Rev Gastroenterol Hepatol. 2013; 10: 656-665Crossref PubMed Scopus (459) Google Scholar Epidemiologic data suggest that NAFLD prevalence is 24% worldwide, with the highest rates reported in South America, Middle East, Asia, United States, and Europe.1Younossi Z. Anstee Q.M. Marietti M. et al.Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat Rev Gastroenterol Hepatol. 2018; 15: 11-20Crossref PubMed Scopus (531) Google Scholar The high rates of NAFLD are thought to be primarily related to the obesity epidemic, especially during childhood and adolescence.1Younossi Z. Anstee Q.M. Marietti M. et al.Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat Rev Gastroenterol Hepatol. 2018; 15: 11-20Crossref PubMed Scopus (531) Google Scholar However, considering NAFLD solely as a consequence of obesity is an oversimplification because NAFLD can also develop in subjects with a normal body mass index (BMI)10Marchesini G. Bugianesi E. Forlani G. et al.Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.Hepatology. 2003; 37: 917-923Crossref PubMed Scopus (1929) Google Scholar or low AT mass, suggesting that AT function rather than AT mass/obesity, could be a main driver of NAFLD. A priori, there is little obvious reason why the liver should have such a dramatic capacity to accumulate fat compared to other organs. This may stem from the fact that AT and liver share an evolutionary origin in which metabolic cells are architecturally organized in close proximity with immune cells and blood vessels in order to coordinate the regulation of metabolic and immune responses.11Hotamisligil G.S. Inflammation and metabolic disorders.Nature. 2006; 444: 860-867Crossref PubMed Scopus (4900) Google Scholar For example, the fat body of Drosophila performs many of the functions of mammalian livers and AT in a single organ and has been used as a model to study obesity and metabolic diseases.11Hotamisligil G.S. Inflammation and metabolic disorders.Nature. 2006; 444: 860-867Crossref PubMed Scopus (4900) Google Scholar,12Musselman L.P. Kuhnlein R.P. Drosophila as a model to study obesity and metabolic disease.J Exp Biol. 2018; 221PubMed Google Scholar In mammals, NAFL itself may represent a maladaptation of mechanisms designed for optimized nutrient storage. First, fasting is a state where neutral lipid accumulation occurs in the liver. Although this is presumed to be as a result of excess release of free fatty acids (FFAs) from the AT, it may be the liver has adapted to store these nutrients and then return the excess back to AT via very-low-density lipoproteins (VLDL) in the fed states, preserving them for later use. Equally, studies in mice of acute overfeeding demonstrate a transient steatosis,13Asterholm I.W. Scherer P.E. Enhanced metabolic flexibility associated with elevated adiponectin levels.Am J Pathol. 2010; 176: 1364-1376Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar which may represent a mechanism to deal with large infrequent influxes of nutrients present in evolution. The transient accumulation of lipid in liver would act to protect other organs when nutrient influx to the organism exceeds the capacity of the body's AT storage rate to deal with acute fat overload. As such, in obesity, NAFL may represent a "least bad" option. Evidence from mice suggests that liver accumulating fat in the context of the severely obese ob/ob mouse model improves liver insulin sensitivity at the cost of greatly worsening systemic insulin sensitivity.14Matsusue K. Haluzik M. Lambert G. et al.Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes.J Clin Invest. 2003; 111: 737-747Crossref PubMed Scopus (408) Google Scholar Overall, the accumulation of large quantities of fat in NAFLD may represent a maladaptation of physiologic systems in the liver designed to buffer short-term changes in nutritional status. We will now discuss the impact on the liver of the body's long-term lipid storage organ, AT, going awry. One idea linking obesity with the development of NAFL is that of AT expandability.15Virtue S. Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the metabolic syndrome—an allostatic perspective.Biochim Biophys Acta. 2010; 1801: 338-349Crossref PubMed Scopus (531) Google Scholar The concept is that each individual possesses an intrinsic limit on their capacity to store lipid in AT. Once this limit is reached, AT can no longer effectively store lipid, thus redirecting them toward other organs, most notably the liver. The mechanisms governing the limit on AT mass are not fully clarified. As AT mass increases dramatically with obesity,16Pouliot M.C. Despres J.P. Lemieux S. et al.Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women.Am J Cardiol. 1994; 73: 460-468Abstract Full Text PDF PubMed Scopus (1523) Google Scholar on a cellular level it leads to both adipocyte hyperplasia and hypertrophy. If not properly supported through appropriate extracellular matrix remodeling and neovascularization, adipocyte hypertrophy can result in adipocyte stress and cell death.17Sun K. Kusminski C.M. Scherer P.E. Adipose tissue remodeling and obesity.J Clin Invest. 2011; 121: 2094-2101Crossref PubMed Scopus (846) Google Scholar Hypertrophic subcutaneous adipocytes have been shown to have a pro-inflammatory gene expression and are associated with greater rates of lipolysis, increased cytokine release, and IR.18Hotamisligil G.S. Johnson R.S. Distel R.J. et al.Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein.Science. 1996; 274: 1377-1379Crossref PubMed Scopus (588) Google Scholar,19Hotamisligil G.S. Shargill N.S. Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.Science. 1993; 259: 87-91Crossref PubMed Google Scholar Equally, intra-abdominal (visceral) adipocyte hypertrophy has been associated with dyslipidemia,20Hoffstedt J. Arner E. Wahrenberg H. et al.Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity.Diabetologia. 2010; 53: 2496-2503Crossref PubMed Scopus (125) Google Scholar suggested to be through excessive net delivery of FFAs to the portal circulation. The AT expandability hypothesis is attractive, as it explains several clinical and epidemiologic observations regarding NAFLD progression. Not all individuals present with NAFLD at the same BMI. The AT expandability hypothesis would postulate different individuals have different intrinsic limits on capacity to expand their AT depots. On reaching their limits at different levels of adiposity, they begin to develop IR and subsequently NAFLD. Equally, epidemiologically, different populations exhibit different susceptibilities to obesity-associated metabolic complications. Asian populations from the Indian and Chinese communities exhibit metabolic complications found in obese Caucasians at comparable frequencies when reaching a BMI of 28 kg/m2 rather than 30 kg/m2.21WHO Expert ConsultationAppropriate body-mass index for Asian populations and its implications for policy and intervention strategies.Lancet. 2004; 363: 157-163Abstract Full Text Full Text PDF PubMed Scopus (5453) Google Scholar So-called "lean NAFLD" is mainly prevalent in Asia but affects up to 20% of Europeans and Americans, and is characterized by individuals with normal BMI but an "obese" metabolic phenotype with impaired insulin sensitivity, hyperinsulinemia, and hypertriglyceridemia.22Bugianesi E. Gastaldelli A. Vanni E. et al.Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.Diabetologia. 2005; 48: 634-642Crossref PubMed Scopus (413) Google Scholar,23Musso G. Cassader M. De Michieli F. et al.Nonalcoholic steatohepatitis versus steatosis: adipose tissue insulin resistance and dysfunctional response to fat ingestion predict liver injury and altered glucose and lipoprotein metabolism.Hepatology. 2012; 56: 933-942Crossref PubMed Scopus (80) Google Scholar Although the causes are not fully delineated, it is believed that lean NAFLD arises as a consequence of a combination of unhealthy lifestyles (diets enriched in fructose, or westernized pattern of nutrition; sedentary habits), genetic risk factors, and abnormal AT function (Figure 1). In contrast, different studies have suggested that lean NASH subjects are characterized by an early impairment of white AT expandability and flexibility, increased AT IR and FFA release, and are more prone to develop NASH.22Bugianesi E. Gastaldelli A. Vanni E. et al.Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.Diabetologia. 2005; 48: 634-642Crossref PubMed Scopus (413) Google Scholar,23Musso G. Cassader M. De Michieli F. et al.Nonalcoholic steatohepatitis versus steatosis: adipose tissue insulin resistance and dysfunctional response to fat ingestion predict liver injury and altered glucose and lipoprotein metabolism.Hepatology. 2012; 56: 933-942Crossref PubMed Scopus (80) Google Scholar A lipodystrophy-like phenotype in the general population (with limited subcutaneous fat mass and expansion of different visceral AT deposits and/or lower body fat mass) may therefore explain part of the metabolic unhealthiness in lean individuals.24Stefan N. Schick F. Haring H.U. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans.Cell Metab. 2017; 26: 292-300Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar,25Bjorndal B. Burri L. Staalesen V. et al.Different adipose depots: their role in the development of metabolic syndrome and mitochondrial response to hypolipidemic agents.J Obes. 2011; 2011: 490650Crossref PubMed Scopus (167) Google Scholar The most extreme example of limited AT expansion is exhibited by individuals with either genetic or defects in AT development. These disorders are known as lipodystrophies. While a complex and heterogenous population, lipodystrophic individuals are characterized by low or no fat mass. Despite being lean, they are variably, and in some cases extremely, insulin resistant and exhibit much higher rates of NAFL, NASH progression, and cardiometabolic complications than would be expected based simply on their degree of adiposity.26Polyzos S.A. Perakakis N. Mantzoros C.S. Fatty liver in lipodystrophy: a review with a focus on therapeutic perspectives of adiponectin and/or leptin replacement.Metabolism. 2019; 96: 66-82Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The clinical observations regarding patients with lipodystrophies are further supported by mouse models of lipodystrophy. For example, A/ZIP mice carry a transgene that causes a complete failure in AT formation, and develop substantial NAFL, with liver weights more than double those of controls.27Moitra J. Mason M.M. Olive M. et al.Life without white fat: a transgenic mouse.Genes Dev. 1998; 12: 3168-3181Crossref PubMed Google Scholar However, this picture is more complex; the absence of AT also causes a lack of adipokines, with dramatic effects on whole-body metabolism and IR. For example, studies show that treating lipodystrophic patients with leptin can reverse hyperphagia and result in amelioration of metabolic abnormalities.28Petersen K.F. Oral E.A. Dufour S. et al.Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy.J Clin Invest. 2002; 109 (s): 1345-1350Crossref PubMed Google Scholar Furthermore, mice lacking white fat also lack leptin and are hyperphagic.28Petersen K.F. Oral E.A. Dufour S. et al.Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy.J Clin Invest. 2002; 109 (s): 1345-1350Crossref PubMed Google Scholar Treating such mice with leptin ameliorates both IR and reduces NAFLD.29Cortes V.A. Cautivo K.M. Rong S. et al.Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2–/– lipodystrophic mice independent of hepatocyte leptin receptors.J Lipid Res. 2014; 55: 276-288Crossref PubMed Scopus (0) Google Scholar The degree of steatosis in the liver is determined by the flux of fat through the hepatocyte. The levels of fat in the liver are set by the quantity of lipid that the liver either produces or takes up from the bloodstream, and the capacity for the liver to export or burn it. If either side of the liver fat equation changes, it will lead to an increase or decrease in liver fat levels. Once uptake/production of fat comes back into equilibrium with export/oxidation, a new steady-state concentration of liver fat will be established. We can therefore consider steatosis through the prism of turnover equations.30Claydon A.J. Beynon R. Proteome dynamics: revisiting turnover with a global perspective.Mol Cell Proteomics. 2012; 11: 1551-1565Crossref PubMed Scopus (58) Google Scholar The degree of steatosis in the liver can be considered as the pool size in a turnover equation, where rate of synthesis (ksyn) is composed of de novo lipogenesis (DNL), hepatic FFA uptake, and lipoprotein uptake. In turn, rate of degradation (kdeg) comprises the processes of fatty acid oxidation and export. The equation for pool size, [P], is [P] = ksyn/kdeg, where ksyn has the units of mass and kdeg is expressed as fractional removal over time. The fat present in the liver is constantly turning over and the amount of fat accumulated can be altered by changes in ksyn, kdeg, or both. If ksyn increases without a change in kdeg then the pool size expands until the 2 processes balance again. For example, if ksyn for the whole liver is 2 mg/g liver/h and is 2%/g liver/h, then the pool size will be 2/0.02 = 100 mg/g liver; the liver will contain 10% fat. If ksyn increases 2-fold to 4 mg/g liver/h, the pool size will double to 4/0.02 = 200 mg/g and the liver will contain 20% fat (Figure 2). Thus, while many mechanisms may exist to explain how ksyn or kdeg may be changed, the absolute degree of steatosis represents a turnover issue. Therefore, if fluxes of fat to the liver increase, even in states of neutral energy balance, unless they are matched by active increases in fatty acid oxidation or export (collectively kdeg), then steatosis will occur (Figure 2, middle panel). One immediate consequence of flux model is that under physiologic conditions if ksyn is increased, export of lipid from the liver will increase even if no active change in kdeg occurs. Several studies have found that this is the case. In healthy subjects (<5% liver fat) FFA fluxes to the liver correlate with VLDL secretion31Mittendorfer B. Yoshino M. Patterson B.W. et al.VLDL Triglyceride kinetics in lean, overweight, and obese men and women.J Clin Endocrinol Metab. 2016; 101: 4151-4160Crossref PubMed Scopus (0) Google Scholar and intrahepatic TG levels (pool size) correlates with VLDL secretion, consistent with kdeg being a fraction of the pool disposed per unit of time. In NAFL, this relationship between TG pool size and VLDL secretion breaks down,31Mittendorfer B. Yoshino M. Patterson B.W. et al.VLDL Triglyceride kinetics in lean, overweight, and obese men and women.J Clin Endocrinol Metab. 2016; 101: 4151-4160Crossref PubMed Scopus (0) Google Scholar,32Lytle K.A. Bush N.C. Triay J.M. et al.Hepatic fatty acid balance and hepatic fat content in severely obese humans.J Clin Endocrinol Metab. 2019; 104: 6171-6181Crossref PubMed Scopus (0) Google Scholar suggesting an upper limit on TG export capacity from liver.33Adiels M. Taskinen M.R. Packard C. et al.Overproduction of large VLDL particles is driven by increased liver fat content in man.Diabetologia. 2006; 49: 755-765Crossref PubMed Scopus (427) Google Scholar Conversely, a setting of an inherently low VLDL production will also change steatosis levels, assuming ksyn remains constant. When overexpressed, the PNPLA3 polymorphism I148M results in low VLDL secretion rates in cultured hepatocytes. In vivo, however, VLDL secretion rates from carriers of the I148M polymorphism remain constant in absolute terms, but represent a lower proportion of the total lipid pool (consistent with the concept kdeg is fractional). In this setting, consistent with our model, the consequence of a genetic limit on kdeg is not reduced VLDL production, but an expansion of the pool size until a new equilibrium is reached34Pirazzi C. Adiels M. Burza M.A. et al.Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro.J Hepatol. 2012; 57: 1276-1282Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar (Figure 2, right panel). Equally, the same applies to the E167K substitution in TM6SF2, resulting in decreased VLDL secretion and an increased propensity toward a fibrotic liver phenotype,35Liu Y.L. Reeves H.L. Burt A.D. et al.TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease.Nat Commun. 2014; 5: 4309Crossref PubMed Scopus (244) Google Scholar,36Sookoian S. Castano G.O. Scian R. et al.Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity.Hepatology. 2015; 61: 515-525Crossref PubMed Scopus (101) Google Scholar but a lower cardiovascular risk.37Dongiovanni P. Petta S. Maglio C. et al.Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease.Hepatology. 2015; 61: 506-514Crossref PubMed Scopus (207) Google Scholar Recently, Helsley et al38Helsley R.N. Venkateshwari V. Brown A.L. et al.Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease.Elife. 2019; 8Crossref PubMed Scopus (4) Google Scholar have shown that MBOAT7-driven acylation of lysophosphatidylinositols in humans is protective against obesity-associated NAFLD progression by altering hepatic lipid droplet flux. In the following sections, we discuss how changes in AT may drive fatty acid fluxes to liver beyond its export capacity. AT is critical for determining the fluxes of lipid to the liver in both the fasting and fed states. Importantly, multiple processes that become dysregulated in obese AT are able to affect the delivery of fatty acids to the liver. Basal and postprandial fatty acid turnover rates in obese individuals have been reported to be elevated on a whole-organism level39Jensen M.D. Haymond M.W. Rizza R.A. et al.Influence of body fat distribution on free fatty acid metabolism in obesity.J Clin Invest. 1989; 83: 1168-1173Crossref PubMed Google Scholar,40McQuaid S.E. Hodson L. Neville M.J. et al.Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition?.Diabetes. 2011; 60: 47-55Crossref PubMed Scopus (189) Google Scholar and particularly in the context of upper body obesity,41Roust L.R. Jensen M.D. Postprandial free fatty acid kinetics are abnormal in upper body obesity.Diabetes. 1993; 42: 1567-1573Crossref PubMed Scopus (0) Google Scholar,42Guo Z. Hensrud D.D. Johnson C.M. et al.Regional postprandial fatty acid metabolism in different obesity phenotypes.Diabetes. 1999; 48: 1586-1592Crossref PubMed Scopus (161) Google Scholar as such obesity represents a state whereby lipid flux to the liver is elevated, promoting an increase in hepatic TG pool size. In the fasted state, the main contributor to the increased fatty acid turnover rate is likely to be lipolysis. Elevations in lipolysis have been suggested to be driven by cell autonomous changes in adipocytes,39Jensen M.D. Haymond M.W. Rizza R.A. et al.Influence of body fat distribution on free fatty acid metabolism in obesity.J Clin Invest. 1989; 83: 1168-1173Crossref PubMed Google Scholar such as an increased prevalence of hypertrophic adipocytes with greater lipolytic rates.43Goldrick R.B. McLoughlin G.M. Lipolysis and lipogenesis from glucose in human fat cells of different sizes. Effects of insulin, epinephrine, and theophylline.J Clin Invest. 1970; 49: 1213-1223Crossref PubMed Google Scholar However, other studies have suggested that net FFA release per adipocyte is low in obesity—instead increased whole-body rates of FFA appearance are driven simply by greater fat mass.40McQuaid S.E. Hodson L. Neville M.J. et al.Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition?.Diabetes. 2011; 60: 47-55Crossref PubMed Scopus (189) Google Scholar This concept is supported by evidence from radiocarbon dating of lipids in AT. The fatty acids in the AT of obese subjects and subjects with familial combined hyperlipidemia are nearly twice as old as those from lean individuals—suggesting obesity and metabolic diseases are characterized by a low lipid turnover per gram of AT.44Arner P. Bernard S. Salehpour M. et al.Dynamics of human adipose lipid turnover in health and metabolic disease.Nature. 2011; 478: 110-113Crossref PubMed Scopus (192) Google Scholar The fed state is more difficult to dissect. Increased fatty acid turnover rates in the fed state can be broadly grouped into either a failure of AT to take up lipids or a failure of insulin to suppress lipolysis. In the fed state, the major source of lipid for storage in AT comes in the form of the TG-rich lipoproteins (chylomicrons and VLDL). The TGs in these lipoproteins are hydrolyzed by lipoprotein lipase, which can have 1 of 2 fates—they can either be transported across the endothelium into the adipocyte to be stored as TG, or they can exit AT as FFAs (a process known as "spillover"). Spillover rates are generally thought to be higher for chylomicrons (approximately 30%) than VLDL (approximately 5%)45Bush N.C. Triay J.M. Gathaiya N.W. et al.Contribution of very low-density lipoprotein triglyceride fatty acids to postabsorptive free fatty acid flux in obese humans.Metabolism. 2014; 63: 137-140Abstract Full Text Full Text PDF PubMed Google Scholar; however, 1 study has reported VLDL spillover could be as high as 70%.46Ruge T. Hodson L. Cheeseman J. et al.Fasted to fed trafficking of Fatty acids in human adipose tissue reveals a novel regulatory step for enhanced fat storage.J Clin Endocrinol Metab. 2009; 94: 1781-1788Crossref PubMed Scopus (94) Google Scholar Intriguingly, spillover from chylomicrons into the circulation has been reported to be higher for women than men, and reduced with obesity, raising doubts about how much this process is responsible for higher FFA fluxes in obese vs lean individuals.47Piche M.E. Parry S.A. Karpe F. et al.Chylomicron-derived fatty acid spillover in adipose tissue: a signature of metabolic health?.J Clin Endocrinol Metab. 2018; 103: 25-34Crossref PubMed Scopus (8) Google Scholar Conversely, splanchnic spillover of FFA into the portal circulation may be more relevant for hepatic delivery. Two studies have reported that visceral fat exhibits high rates of spillover,48Nelson R.H. Basu R. Johnson C.M. et al.Splanchnic spillover of extracellular lipase-generated fatty acids in overweight and obese humans.Diabetes. 2007; 56: 2878-2884Crossref PubMed Scopus (24) Google Scholar and that this is increased in obesity.47Piche M.E. Parry S.A. Karpe F. et al.Chylomicron-derived fatty acid spillover in adipose tissue: a signature of metabolic health?.J Clin Endocrinol Metab. 2018; 103: 25-34Crossref PubMed Scopus (8) Google Scholar Equally, chylomicrons and VLDL may not be fully hydrolyzed, resulting in lipoprotein remnants. These can also be taken up by the liver and potentially contribute to NAFL.49McCullough A. Previs S.F. Dasarathy J. et al.HDL flux is higher in patients with nonalcoholic fatty liver disease.Am J Physiol Endocrinol Metab. 2019; 317