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Centre for Diabetes and Metabolic Medicine Institute of Cell and Molecular Science St. Bartholomew’s and the Royal London School of Medicine and Dentistry Queen Mary University of London London E1 2AT, United Kingdom
Address all correspondence and requests for reprints to: Dr. M. J. Holness, Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, 4 Newark Street, Whitechapel, London E1 2AT, United Kingdom. E-mail: m.j.holness{at}qmul.ac.uk.
The discovery of leptin by Friedman and colleagues in 1994 (1) was a major breakthrough in the study of satiety and obesity. However, the full extent of leptin’s actions to regulate lipid handling by the body has yet to be fully unraveled. A report in this issue of Endocrinology (2) reveals novel insight into the role of leptin in orchestrating lipid handling in both adipose tissue and liver, two of the major players within the body that can limit the excessive circulating lipid delivery that is thought to predispose to major metabolic diseases, through effects mediated via hypothalamic neural circuits and the autonomic nervous system.
Adipose tissue is the main site of lipid storage and release in the body. It has been hypothesized that, as such, adipose tissue can act to buffer lipid levels in the bloodstream (reviewed in Ref. 3), preventing deleterious consequences of excessive lipid delivery to other tissues. The role of adipose tissue as a lipid buffer is demonstrated by the development of hypertriglyceridemia in fatless mice (4) and in lipodystrophy (5, 6), where there is insufficient adipose tissue to provide the necessary buffering capacity. Buffering of lipid fluxes by adipose tissue may also sometimes be impaired in obesity through defects in the ability of adipose tissue to respond rapidly to meals (reviewed in Ref. 3). In that it can remove and either oxidize circulating nonesterified fatty acids (NEFA), derived from adipose tissue, at high rates (predominately forming ketone bodies) or reesterify adipose-derived fatty acids (FA) with their subsequent utilization for hepatic triglyceride (TAG) release as very-low-density lipoproteins (VLDL), the liver also acts as a lipid buffer to some extent. Nevertheless, impaired lipid buffering by adipose tissue, by exposing liver to excessive NEFA, promotes excessive hepatic ketogenesis and/or VLDL secretion. In addition, excessive hepatic NEFA delivery can cause intracellular TAG accumulation. Such ectopic TAG accumulation can be opposed by activation of the lipooxidative transcription factor peroxisome proliferator-activated receptor (PPAR)
. In liver, PPAR promotes FA oxidation and ketogenesis. Conversely, hepatic FA synthesis and TAG accumulation is facilitated by the lipogenic transcription factor sterol regulatory element binding protein (SREBP)-1c.
Leptin, secreted from adipose tissue, decreases lipid accumulation in liver; an acute leptin infusion has been reported to oppose hepatic lipid accumulation by promoting FA oxidation, an action also associated with suppression of hepatic TAG secretion (7). Similarly, hyperleptinemia depletes adipose-tissue TAG, an effect proposed to reflect up-regulation of the oxidation of lipolytically generated FA in situ via a direct autocrine effect of leptin on the adipocytes (8, 9), together with indirect hypothalamic effects, possibly mediated via catecholamine-induced stimulation of lipolysis or cocaine- and amphetamine-regulated transcript-induced increases in lipid oxidation (10). PPAR is necessary for effects of adenovirus-induced systemic hyperleptinemia to deplete body fat (11). Thus, there appears to be a close interaction between the actions of leptin and those of PPAR in the regulation of fat oxidation in both adipose tissue and liver. A recent report in this issue of Endocrinology (2), which examined the effect of centrally administered leptin on gene expression of a range of enzymes and transcription factors in adipose tissue and liver, illustrates these regulatory interactions further. The importance of this paper resides, first, in that the authors considered that peripheral effects of leptin on lipid metabolism in both adipose tissue and liver could be excluded, which is reasonable because circulating leptin levels in intracerebroventricular (icv) leptin-administered rats were unchanged from control, and second, that the set point of inter-tissue cooperation in lipid buffering could be altered via effects of central leptin to exert opposite or tissue-selective effects on expression of PPAR and SREBP-1c (and their downstream targets) in adipose tissue and liver.
The adipo-hepatic axis of FA recycling and the involvement of PPAR in the regulation of this axis can be briefly described as follows. Adipocytes hydrolyze stored TAG in response to lipolytic stimulation. Gene expression of aquaglyceroporin (AQP) 7 (a major glycerol channel in adipose tissue) is enhanced by fasting, facilitating glycerol transfer across the plasma membrane (12); this effect of fasting is dampened by PPAR deficiency (13). Glycerol retention within adipose tissue secondary to AQP7 deficiency promotes expansion of the adipose tissue mass and thus augments adipocyte lipid storage (14, 15). Glyceroneogenesis is also important for adipocyte lipid storage and thus its lipid buffering function. White adipose tissue contains pyruvate carboxylase and the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C) (16), allowing the synthesis of glycerol 3-phosphate from circulating lactate. FA generated by adipose-tissue lipolysis that escape reesterification and are released from adipose tissue into the circulation can be used by the liver as precursors for ketogenesis or VLDL production, the latter after reesterification. Although it is well known that glycerol acts as a precursor for hepatic gluconeogenesis, it is less widely appreciated that hepatic glyceroneogenesis via PEPCK contributes about 65% of hepatic TAG present in plasma as VLDL (17, 18). Several hepatic genes involved in glycerol metabolism, including glycerol transporters AQP3 and -9, are up-regulated by fasting in wild-type mice but not in mice lacking PPAR (19). PPAR deficiency both inhibits gluconeogenesis (20) and also exerts complex effects on hepatic TAG secretion (21).
Enzymes whose gene expression was investigated by Gallardo et al. (2) included the two lipases involved in adipocyte lipolysis, hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), and the glyceroneogenic enzyme PEPCK-C, together with stearoyl-CoA desaturase 1 (SCD1) and 
6-desaturase (D6D). Effects of icv leptin included repression of expression of genes involved in de novo synthesis of FA, together with down-regulation of SCD1 and D6D in liver. It has been reported previously that hepatic expression of SCD1, the enzyme that is considered to be rate limiting for monounsaturated FA synthesis, is high in leptin-deficient ob/ob mice but can be normalized by leptin treatment (22). Furthermore, some of leptin’s effects to reduce ectopic TAG storage in liver have been attributed to leptin-mediated inhibition of SCD1 activity (22). Leptin has also been found to be important in SCD1-mediated effects on insulin sensitivity, because improved insulin sensitivity in SCD1 null mice was reversed in the absence of leptin (23). SCD1-deficient mice show resistance to leptin-deficiency-induced obesity (24). In liver, leptin suppresses SCD1 expression and activity independently of insulin (25), although leptin’s effects on hepatic FA composition have been reported to require insulin signaling (25). It has also been suggested that in states of low or absent leptin, insulin becomes important as a regulator of SCD1 transcription (22, 25). Thus, although interactions between leptin and SCD1 expression have already been reported, the study by Gallardo et al. (2) allows mediation of these effects of leptin to be attributed to effects mediated centrally, most likely via hypothalamic neural circuits and the autonomic nervous system (Fig. 1
).
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and the lipogenic transcription factor SREBP-1c. Suppression of hepatic SCD1 expression was observed in association with a reduction in hepatic SREBP-1c expression and increased hepatic expression of PPAR and PPAR target genes. However, although decreased SCD1 and D6D expression was also observed in response to icv leptin in adipose tissue, decreased gene expression of D6D (which catalyzes the rate-limiting step in conversion of linoleic acid and -linolenic acid into arachidonic acid and eicosapentanoic acid) in adipose tissue was paralleled by decreased PPAR expression, whereas decreased expression of SCD1 in adipose tissue paralleled changes in ChREBP (carbohydrate regulatory element binding protein). In liver, D6D expression can be activated by either SREBP-1c or PPAR, depending on metabolic status (26). Thus, these new data show that central leptin effects use tissue-specific mechanisms to impair lipogenesis by targeting different transcription factors.
Of further interest, central leptin administration decreased PEPCK-C in adipose tissue. This is predicted to contribute to decreased FA recycling to TAG in this tissue. A targeted mutation in the PPAR
2 binding site of the promoter of the PEPCK-C gene in mouse adipose tissue, which abolishes synthesis of TAG-glycerol from pyruvate (27) (see also Ref. 28), causes depletion of adipose tissue TAG and lipodystrophy (27) (see also Ref. 28). Conversely, mice overexpressing PEPCK-C specifically in adipose tissue exhibit more rapid adipose tissue TAG synthesis and become markedly obese (29). This new finding of Gallardo et al. (2) provides a potential molecular mechanism mediated centrally via leptin that may contribute to depletion of adipose-tissue TAG. Thus, an action of leptin centrally to suppress FA reesterification to TAG complements peripheral effects of systemic leptin to augment oxidation of lipolytically generated FA in situ.
Circulating NEFA levels were found to be increased in icv leptin-treated rats, consistent not only with suppression of adipose-tissue glyceroneogenesis, as described above, but also with stimulation of adipose-tissue lipolysis. ATGL is rate limiting for initiation of TAG catabolism. The existence of ATGL in adipose tissue has been inferred from findings that although ß-agonist-induced lipolysis is lower in HSL null mice, adipocyte-stored TAG can be mobilized, and basal lipolysis is normal (30, 31). Inactivation of the ATGL gene in mice drastically reduces ß-adrenergic-stimulated lipolysis, whereas basal lipolysis is unchanged (32). ATGL expression is enhanced by fasting (33), in part via increased PPAR signaling (13). The new data provided by Gallardo et al. (2) suggest that expression of ATGL in adipose tissue can be controlled by hypothalamic mechanisms and that leptin can regulate adipocyte lipolysis via such a mechanism, thereby contributing to its feedback regulation of adipose tissue mass.
Considerable reesterification of FA occurs even during periods of active lipolysis; in man, recycling may be as high as 40% (34). Intracellular recycling (primarily FA reesterification in white adipose tissue) represents about 20–30% of total recycling, whereas nonadipose tissue recycling (primarily hepatic) accounts for approximately 50% of FA reesterification in healthy adults after an overnight fast. In healthy human newborn infants, 75% of the FA released by lipolysis is recycled (35). Thus, changes in both intracellular cycling of FA in adipose tissue and inter-tissue (adipocyte-liver) FA cycling are potentially important in whole-body metabolic homeostasis. As with any cycle, the speed of cycling is predicted to increase sensitivity of net flux to regulation by external agents. Thus, the data presented by Gallardo et al. (2) may imply that, by changing PPAR expression reciprocally in liver (increased) and adipose tissue (decreased), central leptin administration could augment sensitivity of adipo-hepatic FA cycling to regulation, changing the set point of the cycle to enhance lipid clearance by liver at the expense of adipocyte lipid storage. More studies dealing with the projections from leptin-sensitive regions of the central nervous system to liver and adipose tissue are clearly warranted.
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Footnotes |
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Abbreviations: AQP, Aquaglyceroporin; ATGL, adipose triglyceride lipase; D6D, 6-desaturase; FA, fatty acid(s); HSL, hormone-sensitive lipase; icv, intracerebroventricular; NEFA, nonesterified fatty acids; PEPCK-C, cytosolic form of phosphoenolpyruvate carboxykinase; PPAR, peroxisome proliferator-activated receptor; SCD1, stearoyl-CoA desaturase 1; SREBP, sterol regulatory element binding protein; TAG, triglyceride; VLDL, very-low-density lipoproteins.
Received September 13, 2007.
Accepted for publication September 19, 2007.
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is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. Proc Natl Acad Sci USA 99:11848–11853 governs glycerol metabolism. J Clin Invest 114:94–103[CrossRef][Medline] null mice is due to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression. FEBS Lett 475:163–166[CrossRef][Medline]-deficient mice. J Lipid Res 42:328–3375- and 6-desaturase gene expression by SREBP-1 and PPAR. J Lipid Res 43:107–114-binding site in the gene for the cytosolic form of phosphoenolpyruvate carboxykinase reduces adipose tissue size and fat content in mice. Proc Natl Acad Sci USA 99:625–630
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