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Dichotomous roles of leptin and adiponectin as enforcers against lipotoxicity during feast and famine.
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Science is marked by the death of dogmas; the discovery that adipocytes are more than just lipid-storing cells but rather produce potent hormones is one such example that caught physiologists by surprise and reshaped our views of metabolism. While we once considered the adipocyte as a passive storage organ for efficient storage of long-term energy reserves in the form of triglyceride, we now appreciate the general idea (once a radical one) that adipocytes are sophisticated enough to have potent endocrine functions. Over the past two decades, the discoveries of these adipose-derived factors ("adipokines") and their mechanistic actions have left us marveling at and struggling to understand the role these factors serve in physiology and the pathophysiology of obesity and diabetes. These hormones may serve an integral role in protecting nonadipose tissues from lipid-induced damage during nutrient-deprived or replete states. As such, adipocytes deliver not only potentially cytotoxic free fatty acids but, along with these lipids, antilipotoxic adipokines such as leptin, adiponectin, and fibroblast growth factor 21 that potently eliminate excessive local accumulation of these lipids or their conversion to unfavorable sphingolipid intermediates.
Roger H Unger; Philipp E Scherer; William L Holland
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Title:  Molecular biology of the cell     Volume:  24     ISSN:  1939-4586     ISO Abbreviation:  Mol. Biol. Cell     Publication Date:  2013 Oct 
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Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8549 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8549.
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Journal ID (nlm-ta): Mol Biol Cell
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ISSN: 1939-4586
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© 2013 Unger et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (
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Dichotomous roles of leptin and adiponectin as enforcers against lipotoxicity during feast and famine
Roger H. Ungera
Philipp E. Schererab
William L. Hollanda1
Keith G. Kozminski Role: Monitoring Editor
aTouchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390–8549
bDepartment of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390–8549
University of Virginia
Correspondence: 1Address correspondence to: William L. Holland (


Understanding the mechanisms of adipose-derived hormones is a major challenge. Notably, the specific manner in which leptin (the first adipokine to be described) was discovered posed a serious teleological conundrum. Leptin was found by positional cloning in ob/ob mice, which are leptin-deficient and in which obesity is reversed by pharmacological replacement with leptin (Halaas et al., 1995). Thus it appeared that the role of leptin was to prevent obesity. This appealing hypothesis was rendered untenable by subsequent studies showing that diet-induced obesity in animals (Frederich et al., 1995) and in humans (Considine et al., 1996) is invariably accompanied by a progressive increase in plasma leptin levels. This not only ended the hope for an anti-obesity hormone, but it left unexplained the true function of this fascinating adipocyte product. Meanwhile, leptin was demonstrated to have multiple actions on multiple targets, but one action, the stimulation of β-oxidation of fatty acids by activating AMP-dependent kinase (AMPK) and increasing the expression of UCP-1 and UCP-2, seems particularly important (Minokoshi et al., 2002).

While the work on leptin was ongoing, adiponectin, a second important adipokine, was described (Scherer et al., 1995). In culture, its actions on fatty acids appear similar to those of leptin: it increases fatty acid oxidation in muscle (Yamauchi et al., 2001). More recent evidence suggests that adiponectin may additionally oppose lipotoxicity by enhancing deacylation of ceramide (Holland et al., 2011), a lipid metabolite heavily implicated in the lipid-induced dysfunction of numerous cell types. Thus both leptin and adiponectin appear to oppose lipotoxicity, the impaired function or survival of a cell due to excess accumulation of lipid and lipid-derived intermediates.


Although leptin and adiponectin have similar lipo-oxidative actions, they differ strikingly in terms of the perturbations that elicit increases in their secretion. Leptin secretion rises acutely during feeding or in response to overnutrition as adipocytes expand in size and number (Unger, 2002). The associated hypoxia caused by undervascularization of the expanding adipose tissue prompts hypoxia-inducible factor (HIF1α) to increase the production of leptin (Sun et al., 2013). Adiponectin secretion is increased during undernutrition and exercise, when adipocytes tend to diminish in size because lipolysis is most active (Miyazaki et al., 2010). These effects are evident even in the diurnal variation of these factors, which displays an interesting dichotomy (R. S. Ahima and P. E. Scherer, personal communication). Leptin levels are highest in the postprandial state at 2 a.m. for rodents and wane prior to consumption of a meal at the onset of the dark cycle. Leptin rises with postprandial increases in circulating fatty acids. By contrast, adiponectin levels are highest in the fasted state; at 2 p.m., adiponectin levels are significantly higher than at the nadir of 12 a.m. Such variations can also be evoked during fasting–feeding experiments, as leptin falls and adiponectin rises when food is withdrawn—a phenomenon reversible by refeeding. (Asterholm and Scherer, 2010). The “yin and yang” of these two adipokines, which are oppositely regulated under essentially all conditions, suggests coordinate regulation, and they may offer complementary approaches to managing lipid flux during feast or famine.

Fibroblast growth factor 21 (FGF21) has recently emerged as a likely modulator of this coordinate regulation of adipokines. Although FGF21 is produced in adipose tissue at significant levels, it was first noted for its abundant production in liver (Nishimura et al., 2000), where fasting or ketogenic diets drive its production in a peroxisome proliferator-activated receptor α (PPARα)-dependent manner (Badman et al., 2007; Inagaki et al., 2007). The 21st member of this FGF superfamily was first reported by Nobuyuki Itoh at Kyoto University (Nishimura et al., 2000) and has received exponential attention since the discovery of its antidiabetic properties in 2005 (Kharitonenkov et al., 2005). This factor is also produced within the adipocyte in response to PPARγ activation and appears to be a critical player in conveying nutritional cues through its adipose-specific actions (Adams et al., 2012; Ding et al., 2012). Notably, both FGF21 (Dutchak et al., 2012; Lin et al., 2013) and adiponectin (Kubota et al., 2006; Nawrocki et al., 2006) appear to play important and intertwining roles in mediating the antidiabetic effects of PPARγ agonists. While adiponectin and FGF21 appear to be key players in the antidiabetic effects of PPARγ agonist, improvements in glucose homeostasis can occur independently of these secreted factors, especially in the presence of suprapharmacological doses of thiazolidine diones (TZDs).

A series of recent reports has established FGF21 as a critical regulator of circulating leptin and adiponectin (Coskun et al., 2008; Adams et al., 2012; Ding et al., 2012). FGF21 rapidly promotes adiponectin secretion (Holland et al., 2013; Lin et al., 2013) and diminishes circulating leptin (Coskun et al., 2008). By enhancing expression of leptin receptors, FGF21 may simultaneously enhance leptin sensitivity in tissues such as liver. Notably, these studies have determined a critical role for leptin on FGF21-induced weight loss (Veniant et al., 2012; Holland et al., 2013), while adiponectin is important for the insulin-sensitizing and glucose-lowering properties of FGF21 (Holland et al., 2013; Lin et al., 2013). Consistent with adiponectin's effect as an antilipotoxic agent, FGF21 lowers ceramides in liver and serum in an adiponectin-dependent manner (Holland et al., 2013).


The foregoing facts suggest to the teleologist an interesting survival advantage provided by the evolution of these adipokines. The likely reason for the evolution of adipocytes is that nonadipocyte cells in the system lack the lipid-storing capacity or tolerance to support their own caloric needs during times of limited nutrient availability. This implies that most of our highly specialized cells, such as pancreatic β cells and cardiomyocytes, have a relatively limited storage capacity for fuel or a relatively high sensitivity to lipotoxic molecules. If there were no endogenous fuel storage capability, even relatively brief periods of caloric limitation would be detrimental. Adipocytes not only solved the problem of storing calories in times of nutrient availability, but solved the problem of damage to lipid-intolerant tissues from either dietary fat during overnutrition or endogenous fatty acids discharged from adipocytes during lipolysis. This suggests that these remarkable lipid-storing cells, exquisite sensors of caloric balance, have arranged to protect vital tissues from accumulation of unutilized lipids, whether derived from food or from the cells’ own lipid stores, by burning away the surplus or promoting the degradation of lipotoxic intermediates.

If lipid influx into a cell exceeds the oxidative or storage capacity of the cell, then lipotoxic lipid intermediates are likely to accumulate (Figure 1). On entry into the cell, lipids receive a CoA charge and are shunted into one of several competing pathways: 1) they can be oxidized in the mitochondria to produce energy equivalents; 2) they can be acylated onto a glycerol backbone to form diacylglycerols, can be stored as triglycerides, or can form membrane phospholipids; or 3) they can be acylated onto a serine backbone, giving rise to the sphingolipid ceramide and its complex derivatives. As each of these pathways competes for substrate, impairments in lipid oxidation promote the enhanced formation of glycerolipid and sphingolipid. While both diacylglycerols and ceramides from these pathways have been implicated in insulin resistance (Savage et al., 2007; Holland and Summers, 2008), ceramide has additionally been invoked as a mediator of cell death, with most reports suggesting proapoptotic mechanisms at play with this intermediate. The unsurpassed storage capacity of adipocytes prevents excess fatty acids from forming lipotoxic intermediates in adipocytes, with excess lipids efficiently forming triglyceride-enriched lipid droplets.

Leptin has potent protective effects on cardiomyocytes. Loss-of-function experiments from leptin-deficient (Mazumder et al., 2004) or leptin receptor–defective rodents show enhanced lipid accumulation and impaired contractile function. By engineering mice with cardiomyocyte-specific overexpression of acyl-CoA synthetase (ACS; Chiu et al., 2001) or GPI-anchored lipoprotein lipase (GPILPL; Yagyu et al., 2003), researchers have described independent models of lipid-induced heart failure. Both models accumulate aberrant ceramides and die prematurely of dilated cardiomyopathy (Chiu et al., 2001; Park et al., 2008). Pharmacologic inhibition of de novo ceramide synthesis using the fungal toxin myriocin prevents the lipid-induced cardiac hypertrophy and contractile dysfunction while extending lifespan in GPILPL transgenic mice (Park et al., 2008). Similarly, overexpressing leptin in ACS transgenic mice diminishes lipid accumulation, prevents cardiac hypertrophy, and restores cardiac function (Lee et al., 2004). Acute treatment of cultured cardiomyocytes with leptin indicates enhanced rates of lipid oxidation likely contribute to the protective mechanisms of the adipokine (Palanivel et al., 2006), and leptin appears to require Janus kinase 2 (Jak2) and p38 mitogen-activated protein (MAP) kinase to induce lipid oxidation (Akasaka et al., 2010).

Adiponectin also has potent cardioprotective effects. Walsh and colleagues have demonstrated in a series of publications that adiponectin ablation exacerbates pressure-overload hypertrophy and ischemia–reperfusion injury, while adenoviral overexpression prevents cardiomyocyte death via mechanisms involving AMPK and cytochrome c oxidase subunit II (COX2) activation (Shibata et al., 2004, 2005). Adiponectin-induced AMPK activation is associated with enhanced lipid oxidation and maintains cardiac output in isolated working-heart models (Fang et al., 2010). During ischemic damage, ceramide is regenerated from sphingomyelin. This alternative source of ceramides offers a remarkable parallel between lipotoxic ceramide production (from de novo synthesis) and ischemic insults (ceramides are regenerated from the most abundant cellular sphingolipid—sphingomyelin). Recent work suggests that adiponectin promotes the deacylation of ceramide via a receptor-dependent mechanism, which represents the most upstream signal evoked by adiponectin (Holland et al., 2011). This finding opened the door to the concept that adiponectin may directly oppose lipotoxicity by targeting the degradation of ceramide—the lipid metabolite most commonly implicated as a mediator of lipotoxic cell death. Even on chow diets, ceramide accumulation is elevated in both the heart and the serum of adiponectin-null mice, while adiponectin-overexpressing transgenic mice display lower levels of the sphingolipid. In “Heart-ATTAC mice,” a model of inducible caspase-8–mediated cardiomyocyte apoptosis, the gene dosage of adiponectin strongly promotes survival of the cardiomyocytes in cell culture or live animals in vivo. Addition of endogenous or exogenous ceramide to cultured neonatal myocytes from these mice revealed a facilitative role for ceramide in promoting caspase-8–dependent apoptosis, as blocking de novo ceramide synthesis with myriocin protected both cardiomyocytes and Heart-ATTAC mice from death. The by-product of the ceramide degradation induced by adiponectin is a cytoprotective sphingolipid base termed sphingosine-1-phosphate (S1P), which is generated in a two-step reaction requiring ceramidase and sphingosine kinase. Delivery of S1P to cardiomyocytes or Heart-ATTAC mice offered essentially complete protection against death. Interestingly, this S1P-dependent protective mechanism evoked by adiponectin parallels previous work showing a reliance on sphingosine kinase–induced S1P formation for adiponectin to promote the COX-2 formation involved in cardiomyocyte protection (Ikeda et al., 2008). Though unclear, protective mechanisms of S1P include activation of several kinases known to promote survival, including AMPK, protein kinase B (Akt), and extracellular signal–related kinase (ERK; Holland et al., 2011).

Adiponectin and leptin both protect against β-cell failure. The Zucker diabetic fatty rat, with mutant alleles encoding the long form of the leptin receptor, develops spontaneous β-cell failure during progression to diabetes. Pancreata from these rats become triglyceride laden, and isolated islets display an enhanced propensity to shunt incoming lipids into sphingolipid synthetic pathways due to overexpression of serine palmitoyltransferase (which catalyzes the first and rate-limiting step in sphingolipid synthesis; Shimabukuro et al., 1997, 1998). These lipid-overloaded islets subsequently die from sphingolipid-dependent lipoapoptosis. Similar lines of work by Poitout and colleagues have also implicated ceramide as an inhibitor of insulin expression in wild-type islets exposed to elevated lipid and glucose, resulting from enhanced ERK, Per-Arnt-Sim kinase, and impaired glucose-stimulated musculo aponeurotic fibrosarcome oncogene homology A (MafA) expression, as well as nuclear exclusion of pancreatic and duodenal homeobox 1 (PDX-1; Hagman et al., 2005; Fontes et al., 2009). Thus sphingolipid accrual in islets can promote either lipotoxic destruction or a glucolipotoxic dysfunction involving impaired insulin transcription, depending on the predisposition of the islet. In leptin-defective rodents, adiponectin overexpression, restoration of leptin action, or targeted inhibition of ceramide synthesis prevents the onset of diabetes and maintains functional islet mass. Adiponectin and its resulting lipid by-product, S1P, potently protect cultured INS-1 β cells from lipid/cytokine-evoked apoptosis by direct addition of ceramide analogues (Holland et al., 2011). Notably, S1P is sufficient to promote AMPK activation in this cell type, while inhibiting ceramidase activity prevents adiponectin from activating AMPK. In vivo, Panic-ATTAC mice, which allow for inducible activation of caspase-8 and result in inducible apoptosis in the mature β cell, are much more susceptible to cell death in the absence of adiponectin and are protected by adiponectin overexpression. In summary, leptin and adiponectin help to maintain functional β-cell mass by diminishing sphingolipid accumulation.

Direct effects of leptin and adiponectin on white adipocytes themselves should not be overlooked when evaluating adipokine effects on ectopic lipid deposition. Leptin, adiponectin, and FGF21 all enhance mitochondrial proliferation in white adipose tissue and whole-body energy expenditure associated with the lipid burning in beige adipocytes (Park et al., 2006; Kim et al., 2007; Fisher et al., 2012). It has been shown in multiple models that adiponectin-mediated enhancements in adipose expansion are highly effective at limiting lipid spillover to other tissues and diminishing formation of lipotoxic metabolites in nonadipose tissues. Thus these adipokines also prevent lipid exposure to cardiomyocytes and β cells by making adipose a more effective storage organ with enhanced lipid-oxidative characteristics.

Could ectopic lipids be the real targets for adipokines? As summarized here, both leptin and adiponectin are capable of increasing fatty acid oxidation and of protecting cells from aberrant ceramide accumulation. This raises the possibility that these adipokines are an integral tool for the lipid-tolerant adipocytes to protect lipid-intolerant nonadipocytes from the lipotoxic consequences of fatty acid spillover. The fact that serum lipids rise as adipocytes expand in size and number as a consequence of overnutrition suggests that leptin's assigned role is the burning of fatty acid overflow, thereby blocking free fatty acid (FFA) entry into lipotoxic pathways, such as those resulting in ceramide formation or the generation of reactive oxygen species. We propose that, in addition to storage of surplus fuel, adipocytes offer nonadipose tissues additional protection against lipotoxicity by secreting a subset of adipokines with antilipotoxic functions. These in turn prompt excess unneeded exogenous or endogenous fatty acids to be oxidized before they can damage the cells in which they are less effectively stored. Thus adipocytes protect nonadipocytes from fatty acid–induced damage by oxidizing surplus lipids unable to be esterified to triglycerides. As such, the adipocyte delivers its toxic cargo (FFAs) along with the antidote (leptin, adiponectin, and FGF21, each made under specific physiological conditions) (Figure 1).



The authors were supported by the National Institutes of Health (NIH; grant K99-DK094973) and an American Heart Association Beginning Grant-in-Aid (12BGI-A8910006) to W.L.H. and NIH grants (R01-DK55758 and P01-DK088761) to P.E.S.

Abbreviations used:
FGF21 fibroblast growth factor 21
PPAR peroxisome proliferator-activated receptor

Adams ACYC,Coskun T,Cheng C,Gimeno R,Luo Y,Kharitonenkov A. The breadth of FGF21’s metabolic actions are governed by FGFR1 in adipose tissueMol MetabolYear: 201223137
Akasaka Y,Tsunoda M,Ogata T,Ide T,Murakami K. Direct evidence for leptin-induced lipid oxidation independent of long-form leptin receptorBiochim Biophys ActaYear: 201018011115112220601111
Asterholm IW,Scherer PE. Enhanced metabolic flexibility associated with elevated adiponectin levelsAm J PatholYear: 20101761364137620093494
Badman MK,Pissios P,Kennedy AR,Koukos G,Flier JS,Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic statesCell MetabYear: 2007542643717550778
Chiu HC,Kovacs A,Ford DA,Hsu FF,Garcia R,Herrero P,Saffitz JE,Schaffer JE. A novel mouse model of lipotoxic cardiomyopathyJ Clin InvestYear: 200110781382211285300
Considine RV,et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humansN Engl J MedYear: 19963342922958532024
Coskun T,Bina HA,Schneider MA,Dunbar JD,Hu CC,Chen Y,Moller DE,Kharitonenkov A. Fibroblast growth factor 21 corrects obesity in miceEndocrinologyYear: 20081496018602718687777
Ding XB-MJ,Owen B,Bookout A,Colbert Coate K,Mangelsdorf D,Kliewer S. βKlotho is required for fibroblast growth factor 21 effects on growth and metabolismCell MetabYear: 20121538739322958921
Dutchak PA,Katafuchi T,Bookout AL,Choi JH,Yu RT,Mangelsdorf DJ,Kliewer SA. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinedionesCellYear: 201214855656722304921
Fang X,Palanivel R,Cresser J,Schram K,Ganguly R,Thong FS,Tuinei J,Xu A,Abel ED,Sweeney G. An APPL1-AMPK signaling axis mediates beneficial metabolic effects of adiponectin in the heartAm J Physiol Endocrinol MetabolYear: 2010299E721E729
Fisher FM,et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesisGenes DevYear: 20122627128122302939
Fontes G,Semache M,Hagman DK,Tremblay C,Shah R,Rhodes CJ,Rutter J,Poitout V. Involvement of Per-Arnt-Sim Kinase and extracellular-regulated kinases-1/2 in palmitate inhibition of insulin gene expression in pancreatic β-cellsDiabetesYear: 2009582048205819502418
Frederich RC,Hamann A,Anderson S,Lollmann B,Lowell BB,Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin actionNat MedYear: 19951131113147489415
Hagman DK,Hays LB,Parazzoli SD,Poitout V. Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of LangerhansJ Biol ChemYear: 2005280324133241815944145
Halaas JL,Gajiwala KS,Maffei M,Cohen SL,Chait BT,Rabinowitz D,Lallone RL,Burley SK,Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese geneScienceYear: 19952695435467624777
Holland WL,et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in miceCell MetabYear: 20131779079723663742
Holland WL,et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectinNat MedYear: 201117556321186369
Holland WL,Summers SA. Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolismEndocr RevYear: 20082938140218451260
Ikeda Y,Ohashi K,Shibata R,Pimentel DR,Kihara S,Ouchi N,Walsh K. Cyclooxygenase-2 induction by adiponectin is regulated by a sphingosine kinase-1 dependent mechanism in cardiac myocytesFEBS LettYear: 20085821147115018339320
Inagaki T,et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21Cell MetabYear: 2007541542517550777
Kharitonenkov A,et al. FGF-21 as a novel metabolic regulatorJ Clin InvestYear: 20051151627163515902306
Kim JY,et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissueJ Clin InvestYear: 20071172621263717717599
Kubota N,et al. Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathwaysJ Biol ChemYear: 20062818748875516431926
Lee Y,Naseem RH,Duplomb L,Park BH,Garry DJ,Richardson JA,Schaffer JE,Unger RH. Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic miceProc Natl Acad Sci USAYear: 2004101136241362915347805
Lin Z,et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in miceCell MetabYear: 20131777978923663741
Mazumder PK,O'Neill BT,Roberts MW,Buchanan J,Yun UJ,Cooksey RC,Boudina S,Abel ED. Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse heartsDiabetesYear: 2004532366237415331547
Minokoshi Y,Kim YB,Peroni OD,Fryer LG,Muller C,Carling D,Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinaseNatureYear: 200241533934311797013
Miyazaki S,Izawa T,Ogasawara JE,Sakurai T,Nomura S,Kizaki T,Ohno H,Komabayashi T. Effect of exercise training on adipocyte-size-dependent expression of leptin and adiponectinLife SciYear: 20108669169820226796
Nawrocki AR,et al. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonistsJ Biol ChemYear: 20062812654266016326714
Nishimura T,Nakatake Y,Konishi M,Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liverBiochim Biophys ActaYear: 2000149220320610858549
Palanivel R,Eguchi M,Shuralyova I,Coe I,Sweeney G. Distinct effects of short- and long-term leptin treatment on glucose and fatty acid uptake and metabolism in HL-1 cardiomyocytesMetabolismYear: 2006551067107516839843
Park BH,Wang MY,Lee Y,Yu X,Ravazzola M,Orci L,Unger RH. Combined leptin actions on adipose tissue and hypothalamus are required to deplete adipocyte fat in lean rats: implications for obesity treatmentJ Biol ChemYear: 2006281402834029117038325
Park TS,et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathyJ Lipid ResYear: 2008492101211218515784
Savage DB,Petersen KF,Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistancePhysiol RevYear: 20078750752017429039
Scherer PE,Williams S,Fogliano M,Baldini G,Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytesJ Biol ChemYear: 199527026746267497592907
Shibata R,et al. Adiponectin-mediated modulation of hypertrophic signals in the heartNat MedYear: 2004101384138915558058
Shibata R,Sato K,Pimentel DR,Takemura Y,Kihara S,Ohashi K,Funahashi T,Ouchi N,Walsh K. Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanismsNat MedYear: 2005111096110316155579
Shimabukuro M,Koyama K,Chen G,Wang MY,Trieu F,Lee Y,Newgard CB,Unger RH. Direct antidiabetic effect of leptin through triglyceride depletion of tissuesProc Natl Acad Sci USAYear: 199794463746419114043
Shimabukuro M,Wang MY,Zhou YT,Newgard CB,Unger RH. Protection against lipoapoptosis of β cells through leptin-dependent maintenance of Bcl-2 expressionProc Natl Acad Sci USAYear: 199895955895619689119
Sun K,Halberg N,Khan M,Magalang UJ,Scherer PE. Selective inhibition of hypoxia-inducible factor 1α ameliorates adipose tissue dysfunctionMol Cell BiolYear: 20133390491723249949
Unger RH. Lipotoxic diseasesAnnu Rev MedYear: 20025331933611818477
Veniant MM,Hale C,Helmering J,Chen MM,Stanislaus S,Busby J,Vonderfecht S,Xu J,Lloyd DJ. FGF21 promotes metabolic homeostasis via white adipose and leptin in micePloS OneYear: 20127e4016422792234
Yagyu H,et al. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathyJ Clin InvestYear: 200311141942612569168
Yamauchi T,et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesityNat MedYear: 2001794194611479627


[Figure ID: F1]

Schematic diagram of factors influencing ectopic lipotoxin accumulation. Mitochondrial lipid oxidation is gated by carnitine palmitoyltransferase 1 (CPT1) via acetyl-CoA carboxylase (ACC). When the abundance of CoA-charged lipids exceeds the capacity to oxidize them, lipids are forced into diacylglycerol or ceramide biosynthetic pathways. Leptin, excreted by adipocytes during feeding and driven by HIF1α, promotes lipid oxidation in adipose and nonadipose tissues to alleviate lipid burden. Adiponectin, with enhanced secretion induced by FGF21 during fasting, directly targets ceramide degradation in target tissues. Adiponectin receptors facilitate the deacylation of ceramide into sphingosine to alleviate toxic effects of ceramide and may also promote lipid oxidation via S1P-induced activation of AMP kinase. Functional adipose tissue protects nonadipocytes from excess lipid by storing excess lipid, limiting lipolysis to times of need, and secreting protective adipokines. Leptin and adiponectin promote mitochondrial biogenesis in adipose, allowing adipose greater capacity to eliminate lipids through energy production.

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