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• W2068859969 abstract "Lipodystrophy and obesity represent extreme and opposite ends of the adiposity spectrum and have typically been attributed to alterations in the expression or function of distinct sets of genes. We previously demonstrated that lipin deficiency impairs adipocyte differentiation and causes lipodystrophy in the mouse. Using two different tissue-specific lipin transgenic mouse strains, we now demonstrate that enhanced lipin expression in either adipose tissue or skeletal muscle promotes obesity. This occurs through diverse mechanisms in the two tissues, with lipin levels in adipose tissue influencing the fat storage capacity of the adipocyte, and lipin levels in skeletal muscle acting as a determinant of whole-body energy expenditure and fat utilization. Thus, variations in lipin levels alone are sufficient to induce extreme states of adiposity and may represent a mechanism by which adipose tissue and skeletal muscle modulate fat mass and energy balance. Lipodystrophy and obesity represent extreme and opposite ends of the adiposity spectrum and have typically been attributed to alterations in the expression or function of distinct sets of genes. We previously demonstrated that lipin deficiency impairs adipocyte differentiation and causes lipodystrophy in the mouse. Using two different tissue-specific lipin transgenic mouse strains, we now demonstrate that enhanced lipin expression in either adipose tissue or skeletal muscle promotes obesity. This occurs through diverse mechanisms in the two tissues, with lipin levels in adipose tissue influencing the fat storage capacity of the adipocyte, and lipin levels in skeletal muscle acting as a determinant of whole-body energy expenditure and fat utilization. Thus, variations in lipin levels alone are sufficient to induce extreme states of adiposity and may represent a mechanism by which adipose tissue and skeletal muscle modulate fat mass and energy balance. Considerable inroads have been made in the last decade toward identifying and characterizing obesity genes expressed in adipose tissue and the hypothalamus. This has led to the formulation of the adipose-hypothalamic axis as a mechanism by which the CNS senses and regulates adipose tissue mass in the periphery (Flier, 2004Flier J.S. Obesity wars: molecular progress confronts an expanding epidemic.Cell. 2004; 116: 337-350Abstract Full Text Full Text PDF PubMed Scopus (926) Google Scholar, Havel, 2001Havel P.J. Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis.Exp. Biol. Med. (Maywood). 2001; 226: 963-977PubMed Google Scholar, Schwartz et al., 2000Schwartz M.W. Woods S.C. Porte Jr., D. Seeley R.J. Baskin D.G. Central nervous system control of food intake.Nature. 2000; 404: 661-671Crossref PubMed Scopus (4652) Google Scholar, Seeley and Woods, 2003Seeley R.J. Woods S.C. Monitoring of stored and available fuel by the CNS: implications for obesity.Nat. Rev. Neurosci. 2003; 4: 901-909Crossref PubMed Scopus (192) Google Scholar). The hypothalamus receives input from afferent adiposity signals, notably leptin, which communicate the status of body fat stores. These signals subsequently act to modulate energy balance to maintain a predetermined level of adiposity. In addition, substantial attention has focused on the neural circuitry upon which these peripheral signals act (Cummings and Schwartz, 2003Cummings D.E. Schwartz M.W. Genetics and pathophysiology of human obesity.Annu. Rev. Med. 2003; 54: 453-471Crossref PubMed Scopus (295) Google Scholar, Seeley et al., 2004Seeley R.J. Drazen D.L. Clegg D.J. The critical role of the melanocortin system in the control of energy balance.Annu. Rev. Nutr. 2004; 24: 133-149Crossref PubMed Scopus (121) Google Scholar). This has led to the identification of a plethora of neurotransmitters and receptor systems with demonstrated and potential roles in regulating food intake and energy expenditure. Efforts have also been applied to identify gene defects underlying conditions of insufficient adipose tissue, as is observed in lipodystrophy. As lipodystrophy and obesity represent extreme ends of the adiposity spectrum, it raises the question of whether genes whose deficiency leads to lipodystrophy may also promote obesity when overexpressed. Consistent with this possibility is the demonstration that some forms of congenital lipodystrophy in humans result from defects in genes with roles in adipogenesis (i.e., PPARG) and fat synthesis/storage (i.e., AGPAT2) (Garg, 2004Garg A. Acquired and inherited lipodystrophies.N. Engl. J. Med. 2004; 350: 1220-1234Crossref PubMed Scopus (620) Google Scholar). However, it is unknown whether genes such as these, which function directly in the adipose tissue, can also cause obesity. Here we demonstrate that lipin, which is expressed primarily in peripheral tissues, possesses this capacity, causing lipodystrophy in its absence and promoting obesity when its levels are enhanced. Lipin, which is encoded by the Lpin1 gene, was identified through positional cloning as the gene mutated in the fatty liver dystrophy (fld) mouse (Péterfy et al., 2001Péterfy M. Phan J. Xu P. Reue K. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin.Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (449) Google Scholar). Null mutation in lipin in these animals confers lipodystrophy, characterized by severe deficiency in adipose tissue mass, development of insulin resistance, and a progressive peripheral neuropathy (Langner et al., 1989Langner C.A. Birkenmeier E.H. Ben-Zeev O. Schotz M.C. Sweet H.O. Davisson M.T. Gordon J.I. The fatty liver dystrophy (fld) mutation. A new mutant mouse with a developmental abnormality in triglyceride metabolism and associated tissue-specific defects in lipoprotein lipase and hepatic lipase activities.J. Biol. Chem. 1989; 264: 7994-8003Abstract Full Text PDF PubMed Google Scholar, Reue et al., 2000Reue K. Xu P. Wang X.P. Slavin B.G. Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene.J. Lipid Res. 2000; 41: 1067-1076Abstract Full Text Full Text PDF PubMed Google Scholar). Lipin is expressed at high levels in metabolically active tissues such as adipose tissue and skeletal muscle and has been shown to interact with proteins having a putative role in nucleocytoplasmic transport in yeast, consistent with its nuclear localization in mammalian cells (Péterfy et al., 2001Péterfy M. Phan J. Xu P. Reue K. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin.Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (449) Google Scholar, Tange et al., 2002Tange Y. Hirata A. Niwa O. An evolutionarily conserved fission yeast protein, Ned1, implicated in normal nuclear morphology and chromosome stability, interacts with Dis3, Pim1/RCC1 and an essential nucleoporin.J. Cell Sci. 2002; 115: 4375-4385Crossref PubMed Scopus (77) Google Scholar). We recently demonstrated that lipin deficiency prevents both diet-induced and genetic obesity and is required upstream of PPARγ for normal adipocyte differentiation (Phan et al., 2004Phan J. Péterfy M. Reue K. Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro.J. Biol. Chem. 2004; 279: 29558-29564Crossref PubMed Scopus (172) Google Scholar). However, it is unclear by examining lipin deficiency whether elevated lipin levels could promote increased adiposity. In addition, the function of lipin in skeletal muscle, where it is expressed at levels comparable to those in adipose tissue, has not yet been explored. To better understand the effect of lipin levels in adipose tissue and skeletal muscle on fat mass and energy metabolism, we have generated and characterized transgenic mouse models with enhanced lipin expression in either mature adipocytes or skeletal muscle. To investigate the role of lipin specifically in mature adipocytes, we generated transgenic mice with enhanced lipin expression specifically in adipose tissue (aP2-lipin Tg) using the 5.4-kb enhancer/promoter region of the aP2 gene, which directs expression in terminally differentiated adipocytes (Graves et al., 1991Graves R.A. Tontonoz P. Ross S.R. Spiegelman B.M. Identification of a potent adipocyte-specific enhancer: involvement of an NF-1-like factor.Genes Dev. 1991; 5: 428-437Crossref PubMed Scopus (117) Google Scholar, Ross et al., 1990Ross S.R. Graves R.A. Greenstein A. Platt K.A. Shyu H.L. Mellovitz B. Spiegelman B.M. A fat-specific enhancer is the primary determinant of gene expression for adipocyte P2 in vivo.Proc. Natl. Acad. Sci. USA. 1990; 87: 9590-9594Crossref PubMed Scopus (183) Google Scholar). In addition, to investigate the effects of enhanced lipin expression in skeletal muscle, we produced a muscle-specific lipin transgenic mouse (Mck-lipin Tg) using the mouse muscle-creatine kinase promoter (Johnson et al., 1989Johnson J.E. Wold B.J. Hauschka S.D. Muscle creatine kinase sequence elements regulating skeletal and cardiac muscle expression in transgenic mice.Mol. Cell. Biol. 1989; 9: 3393-3399Crossref PubMed Scopus (155) Google Scholar, Manchester et al., 1996Manchester J. Skurat A.V. Roach P. Hauschka S.D. Lawrence Jr., J.C. Increased glycogen accumulation in transgenic mice overexpressing glycogen synthase in skeletal muscle.Proc. Natl. Acad. Sci. USA. 1996; 93: 10707-10711Crossref PubMed Scopus (92) Google Scholar). Transgenic mice were generated on a pure C57BL/6J strain background to avoid genetic heterogeneity, and the aP2- and Mck-lipin transgenics were therefore compared to a single combined group of nontransgenic C57BL/6J littermates derived from both colonies. The aP2-lipin Tg mice exhibited a significant 3.5-fold increase in lipin mRNA levels in white adipose tissue and a 20% increase in brown adipose tissue (not statistically significant), with no changes occurring in other tissues examined (skeletal muscle, heart, kidney, intestine; Supplemental Figure S1A available with this article online). In Mck-lipin Tg mice, lipin mRNA levels were increased significantly in skeletal muscle by 3-fold and by 20% in heart (not statistically significant) and were not altered in the other tissues examined (Supplemental Figure S1A). On a chow diet, aP2-lipin Tg mice had body weights similar to non-Tg littermates, whereas Mck-lipin Tg mice exhibited elevated body weight by 10 weeks of age and developed mild obesity by 20 weeks of age (Figure 1A ). When fed a high-fat diet for 6 weeks, both aP2-lipin Tg mice and Mck-lipin Tg mice showed accelerated weight gain, increasing their body weight by ∼40%, compared to a ∼20% increase in non-Tg mice (Figure 1B). The response to the high-fat diet was most pronounced in Mck-lipin Tg mice as these animals gained nearly 18 g and became markedly obese after 6 weeks on the diet (Figures 1B and 1C), compared to a 9.9 g increase in aP2-lipin Tg and 5.3 g increase in non-Tg mice. The accelerated weight gain was reflected by a near doubling of fat pad mass in subcutaneous, gonadal, and retroperitoneal depots in aP2-lipin Tg mice, and more than a doubling of the subcutaneous and near tripling of the gonadal and retroperitoneal fat pad mass in Mck-lipin Tg, compared to non-Tg mice. This was evident both when expressed as absolute fat pad mass (Figure 1D) and as a percent of body weight (Supplemental Figure S1B). Similar to human subjects and other animal models with impaired adipose tissue function, lipin-deficient fld mice develop insulin resistance (Reue et al., 2000Reue K. Xu P. Wang X.P. Slavin B.G. Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene.J. Lipid Res. 2000; 41: 1067-1076Abstract Full Text Full Text PDF PubMed Google Scholar). The occurrence of obesity in Tg mice overexpressing lipin in either adipose tissue or muscle raised the question of whether these animals might also exhibit altered insulin sensitivity. On a chow diet, fasting glucose levels were similar between Mck-lipin Tg and non-Tg mice but were significantly reduced in aP2-lipin Tg mice despite their increased adiposity compared to non-Tg animals (Figure 1E). Feeding a high-fat diet increased glucose levels in both non-Tg and Mck-Tg mice compared to the chow diet, but Mck-Tg animals reached significantly higher levels than the non-Tg mice. Interestingly, aP2-lipin Tg mice maintained significantly lower glucose levels than non-Tg mice on the high fat diet. Fasting plasma insulin levels also revealed distinct effects of lipin overexpression in adipose tissue versus muscle. On a chow diet, Mck-lipin Tg mice had elevated insulin levels compared to the other two strains, which was severely exacerbated by the high-fat diet (Figure 1F). And although the high-fat diet elicited increased insulin levels over the chow values in both non-Tg and aP2-lipin Tg mice, the increase was significantly blunted in the aP2-lipin Tg animals, which reached levels of only 40% of those in non-Tg mice and less than 10% of the levels in Mck-lipin Tg mice. As an indicator of insulin resistance, we calculated the HOMA-IR (homeostatic model of assessment of insulin resistance), which largely mirrored the trends observed in insulin levels among the three strains. Thus, in parallel with the increased adipose tissue mass observed in Mck-lipin Tg mice, these animals exhibited significantly elevated HOMA-IR values on both chow and high-fat diets (Figure 1G). However, despite the increased fat mass in aP2-lipin Tg compared to non-Tg mice, these animals had reduced HOMA-IR values on the high-fat diet, indicating greater insulin sensitivity associated with increased lipin expression specifically in adipose tissue. As we have previously determined that lipin deficiency severely impairs adipocyte differentiation and adipogenic gene expression (Phan et al., 2004Phan J. Péterfy M. Reue K. Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro.J. Biol. Chem. 2004; 279: 29558-29564Crossref PubMed Scopus (172) Google Scholar), we investigated whether enhanced lipin expression promotes adipogenic gene expression. We examined adipose tissue gene expression in aP2-lipin Tg, Mck-lipin Tg, and non-Tg mice on the chow and high-fat diets. We found no effect of either the aP2-lipin or Mck-lipin transgenes on PPARγ or aP2 expression levels, indicating that obesity resulting from enhanced lipin expression in mature adipocytes or muscle is not associated with increased adipogenic gene expression (Figure 2A ). Since the aP2-regulatory elements direct lipin expression in mature adipocytes but not preadipocytes, these results are consistent with a role for lipin in mature adipocytes that is distinct from its requirement in preadipocytes for induction of adipogenic gene expression. Next, we examined the expression of lipid synthesis and storage genes in adipose tissue from Tg mice fed chow and high-fat diets. In chow-fed aP2-lipin Tg mice, we found a 3.9-fold increase compared to non-Tg mice in expression of DGAT (acyl CoA:diacylglycerol acyltransferase), a key enzyme in triglyceride synthesis (Figure 2B). After 6 weeks of the high-fat diet, adipose tissue from aP2-lipin Tg animals also exhibited elevated expression levels of acetyl-CoA carboxylase-1 (ACC-1), phosphoenolpyruvate carboxykinase (PEPCK), as well as DGAT, by a factor of 4.5, 2.6, and 3.9, respectively. Expression of fat synthesis/storage genes was not increased in adipose tissue from Mck-lipin Tg on either diet, indicating that enhanced expression of these genes in aP2-lipin Tg mice likely reflects elevated lipin levels in adipose tissue rather than increased adiposity per se. Previously, we showed that lipin-deficient mice exhibit normal food intake but reduced feed conversion efficiency (Phan et al., 2004Phan J. Péterfy M. Reue K. Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro.J. Biol. Chem. 2004; 279: 29558-29564Crossref PubMed Scopus (172) Google Scholar). Similarly, food intake was not altered in aP2-lipin Tg or Mck-lipin Tg compared to non-Tg mice on either a chow (data not shown) or high-fat diet (Figure 3A ). We did, however, observe an increase in feed conversion efficiency (weight gain per food intake normalized to food absorption; see Experimental procedures) in both transgenic strains (Figure 3B). These findings suggested that lipin levels may modulate energy expenditure. To investigate this possibility, we examined oxygen consumption in fld, aP2-lipin Tg, and Mck-lipin Tg mice on chow and high-fat diets. Compared to wild-type mice, fld mice fed a chow diet exhibited significantly higher oxygen consumption in both light (∼10% increase) and dark (∼15% increase) phases (Figure 3C). The increase in oxygen consumption on the high-fat diet was approximately 20% and 15% during the light and dark phases, respectively (Supplemental Figure S2A). The opposite effect was seen in Mck-lipin Tg mice. Thus, on a chow diet, Mck-lipin Tg mice consumed about 10% less oxygen during both the light and dark cycles compared to non-Tg mice (Figure 3D). On the high-fat diet, energy expenditure in Mck-lipin Tg compared to non-Tg mice was reduced further by 15% in both light and dark phases (Supplemental Figure S2B). Despite enhanced adiposity in aP2-lipin Tg mice, there was no significant difference in energy expenditure, though there was a trend toward slightly reduced oxygen consumption on both chow and high-fat diets (Figure 3D and Supplemental Figure S2B). While the reduction in energy expenditure in the aP2-lipin Tg mice was not statistically significant, it is possible that the modest reductions consistently observed nevertheless contribute to the positive energy balance in these animals. Concordant with the increased energy expenditure in fld mice, body temperature was elevated in these animals (Figure 3E). This could not be accounted for by increased thermogenesis due to elevated uncoupling protein-1 (UCP-1) expression in brown adipose tissue, as fld mice express normal levels of UCP-1 mRNA (Figure 3F). In contrast to lipin-deficient mice, body temperature was decreased in Mck-lipin Tg mice but was not different from control values in aP2-lipin Tg mice. This was true on either a chow (Figure 3E) or high-fat diet (data not shown). As with the lipin-deficient mice, the altered body temperature in lipin Tg mice could not be explained by altered UCP-1 expression in brown adipose tissue on a chow (Figure 3F) or high-fat diet (data not shown). Thus, lipin levels in skeletal muscle but not adipose tissue appear to be a significant determinant of energy expenditure. We also assessed the respiratory quotient (RQ) in lipin-deficient and lipin transgenic mice under ad libitum fed, fasting, and re-fed conditions to determine the effect of lipin levels on whole-body carbohydrate versus fat utilization. During ad libitum feeding conditions, RQ values were lower in fld compared to wild-type mice, indicating a preference for fat utilization in fld mice during conditions of continual food availability (Figure 4A ). In contrast, ad libitum fed RQ values were higher in Mck-lipin Tg, but not aP2-lipin Tg, when compared to non-Tg mice (Figure 4B). Upon fasting, RQ values in humans and mice normally decrease to indicate a shift away from glucose and toward fatty acid utilization. Although RQ values declined in fld mice after an overnight fast, they remained higher than wild-type mice (Figure 4A). This likely reflects the decreased availability of fatty acid substrates in lipin-deficient mice due to impaired adipose tissue development. This is supported by the observation that re-feeding for 6 hr re-established the preference for fat utilization in fld compared to wild-type mice observed during ad libitum feeding conditions (Figure 4A). In contrast to lipin-deficient mice, the Mck-lipin Tg mice exhibited elevated RQ under all conditions, indicating a failure to utilize fat as efficiently as non-Tg or aP2-lipin Tg mice (Figure 4B). Even upon fasting, Mck-lipin Tg mice maintained higher RQ values than non-Tg and aP2-lipin Tg mice, which were similar to each other. The abundance of fat stores in Mck-lipin Tg mice suggests that higher fasting RQ in these mice may reflect resistance to fasting-induced lipolysis and β-oxidation rather than decreased substrate availability (Bezaire et al., 2001Bezaire V. Hofmann W. Kramer J.K. Kozak L.P. Harper M.E. Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(−/−) and wild-type mice.Am. J. Physiol. Endocrinol. Metab. 2001; 281: E975-E982PubMed Google Scholar, Kelley et al., 1999Kelley D.E. Goodpaster B. Wing R.R. Simoneau J.A. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss.Am. J. Physiol. 1999; 277: E1130-E1141PubMed Google Scholar, Owen et al., 1979Owen O.E. Reichard Jr., G.A. Patel M.S. Boden G. Energy metabolism in feasting and fasting.Adv. Exp. Med. Biol. 1979; 111: 169-188Crossref PubMed Scopus (76) Google Scholar). The abnormal RQ values observed in fld and MCK-lipin Tg mice cannot be attributed to differences in long-term or acute food consumption, as food intake was similar to that of wild-type and nontransgenic animals (Figure 3, Figure 4C and Phan et al., 2004Phan J. Péterfy M. Reue K. Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro.J. Biol. Chem. 2004; 279: 29558-29564Crossref PubMed Scopus (172) Google Scholar ). Thus, whereas lipin deficiency leads to an increase in the proportional utilization of fatty acid compared to glucose substrates for oxidation, enhanced lipin levels in skeletal muscle produced the opposite effect of decreased fatty acid utilization. To examine the molecular basis for altered fuel partitioning in lipin-deficient and lipin transgenic mice, we measured the expression of several fatty acid metabolism genes in skeletal muscle. In fld compared to wild-type mice, we observed nearly double the levels of fatty acid oxidation gene expression, including carnitine palmitoyl transferase-1 (CPT-1) and acyl-CoA-oxidase (AOX), and a 50% reduction in acetyl-CoA-carboxylase (ACC), responsible for production of malonyl CoA, which inhibits fatty acid oxidation (Figure 5A ). On the other hand, expression levels for genes associated with lipid storage, such as DGAT and ATP-citrate lyase (ACL), were decreased in fld muscle. Examination of Mck-lipin Tg mice revealed an opposite pattern of expression compared to fld mice, with nearly a 50% reduction in expression of fatty acid oxidation genes (CPT-1 and AOX), and double to triple the non-Tg levels of ACC, DGAT, and ACL (Figure 5B). We did not observe any differences in fatty acid metabolism gene expression in skeletal muscle of aP2-lipin Tg compared to non-Tg mice (Figure 5B). Thus, associated with the observed differences in RQ measurements are changes in muscle gene expression that favor fatty acid utilization over storage in fld mice, with an opposite expression profile that favors fatty acid storage in Mck-lipin Tg mice. Data from our fld and Mck-lipin Tg mice strongly implicate lipin levels in skeletal muscle as a determinant of energy expenditure and fatty acid utilization. To ascertain whether the altered energy metabolism observed in fld mice is attributable specifically to the lack of lipin in muscle (as opposed to adipose or other tissues where lipin is expressed), we restored lipin expression in skeletal muscle of fld mice by introducing the Mck-lipin transgene. The resulting fld-Mck-lipin Tg mice exhibit lipin deficiency in all tissues except skeletal muscle, where lipin levels are increased by a factor of 2.6 above wild-type levels, similar to those in Mck-lipin Tg animals (data not shown). Examination of energy expenditure in fld-Mck-lipin Tg mice revealed decreased oxygen consumption compared to fld mice, with values only slightly higher than those observed in Mck-lipin Tg mice (Figure 6A ). In addition, body temperature was reduced and RQ values were elevated to levels observed in Mck-lipin Tg mice by restoration of lipin expression exclusively in muscle of fld mice (Figures 6B and 6C). This was accompanied by corresponding changes in gene expression in skeletal muscle from fld-Mck-lipin Tg mice, showing decreased expression of CPT-1 and AOX and increased expression of ACC, ACL, and DGAT (Figure 6D). Interestingly, despite decreased energy expenditure and suppression of fatty acid utilization in fld-Mck-lipin Tg mice, these mice exhibited no increase in body weight or adiposity compared to fld mice and were resistant to diet-induced obesity (Figures 6E and 6F). This is attributable in part to the absence of lipin in the adipose tissue of fld-Mck-lipin Tg mice, impairing the capacity to develop normal adipocytes and thus store fat. Consistent with this interpretation, PPARγ, aP2, and DGAT mRNA levels were dramatically reduced in adipose tissue from fld-Mck-lipin Tg (Figure 6G). Overall, these results establish lipin levels in skeletal muscle as a major determinant of whole-body energy expenditure and fatty acid utilization and confirm the requirement for lipin in adipose tissue in order to develop normal fat mass. Our studies in lipin-deficient and lipin transgenic mice reveal that modulation of lipin levels alone is sufficient to cause dramatic shifts in adiposity, resulting in either lipodystrophy in the absence of lipin or obesity due to enhanced lipin expression in either adipose tissue or skeletal muscle. Moreover, these studies reveal that lipin levels in two metabolically important tissues, adipose tissue and skeletal muscle, modulate fat mass by distinct mechanisms. The effects of altered lipin levels on adiposity are opposite to those conferred by altered leptin levels, where leptin deficiency causes obesity and elevated leptin levels produced by overexpression in liver cause a lean phenotype (Friedman, 2002Friedman J.M. The function of leptin in nutrition, weight, and physiology.Nutr. Rev. 2002; 60 (discussion S68–S84, S85–S87): S1-S14Crossref PubMed Scopus (363) Google Scholar, Ogawa et al., 1999Ogawa Y. Masuzaki H. Hosoda K. Aizawa-Abe M. Suga J. Suda M. Ebihara K. Iwai H. Matsuoka N. Satoh N. et al.Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin.Diabetes. 1999; 48: 1822-1829Crossref PubMed Scopus (171) Google Scholar ). However, although both lipin and leptin are synthesized in peripheral tissues, a major distinction is that leptin exerts its primary effects through signaling in the hypothalamus, while lipin is not secreted and therefore exerts its effects on adiposity and energy balance through an as yet unknown intracellular function in adipose tissue and skeletal muscle. In adipose tissue, we previously demonstrated that lipin expression in the adipocyte occurs in two phases—a transient induction in preadipocytes shortly after stimulation with adipogenic factors and a second wave of expression in mature adipocytes that have accumulated triglyceride (Phan et al., 2004Phan J. Péterfy M. Reue K. Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro.J. Biol. Chem. 2004; 279: 29558-29564Crossref PubMed Scopus (172) Google Scholar). The requirement for lipin in pre-adipocytes for normal adipocyte differentiation contributes to the lack of normal fat accumulation in fld and fld-Mck-lipin Tg mice, but the role of lipin in mature adipocytes could not be addressed in lipin-deficient animals as their adipose tissue remains immature. Using the aP2-lipin transgene to drive lipin expression in mature adipocytes, we show that enhanced lipin expression in mature adipocytes augments adiposity and accelerates diet-induced obesity. This is in part due to enhanced feed efficiency and increased triglyceride synthesis. The aP2-lipin transgene did not, however, affect adipogenic gene expression, consistent with the proposal that the two temporal phases of lipin gene expression have distinct roles in adipocyte biology. Skeletal muscle, by virtue of its mass, is a major determinant of whole-body fatty acid utilization. However, the identification of genes that regulate energy expenditure and thermogenesis in this organ has been elusive. The discovery of UCP-3 provided an attractive candidate for a modulator of energy expenditure in skeletal muscle. UCP-3 is highly expressed in skeletal muscle and when overexpressed, produces lean and hyperphagic mice (Clapham et al., 2000Clapham J.C. Arch J.R. Chapman H. Haynes A. Lister C. Moore G.B. Piercy V. Carter S.A. Lehner I. Smith S.A. et al.Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean.Nature. 2000; 406: 415-418Crossref PubMed Scopus (508) Google Scholar, Son et al., 2004Son C. Hosoda K. Ishihara K. Bevilacqua L. Masuzaki H. Fushiki T. Harper M.E. Nakao K. Reduction of diet-induced obesity in transgenic mice overexpressing uncoupling protein 3 in skeletal muscle.Diabetologia. 2004; 47: 47-54Crossref PubMed Scopus (44) Google Scholar ). However, the lack of an observable phenotype in mice deficient for UCP-3 indicated an alternative function for UCP-3 in this tissue (Gong et al., 2000Gong D.W. Monemdjou S. Gavrilova O. Leon L.R. Marcus-Samuels B. Chou C.J. Everett C. Kozak L.P. Li C. Deng C. et al.Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3.J. Biol. Chem. 2000; 275: 16251-16257Crossref PubMed Scopus (334) Google Scholar, Vidal-Puig et al., 2000Vidal" @default.
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• W2068859969 title "Lipin, a lipodystrophy and obesity gene" @default.
• W2068859969 cites W147957900 @default.
• W2068859969 cites W1523366628 @default.
• W2068859969 cites W1561443084 @default.
• W2068859969 cites W1854143160 @default.
• W2068859969 cites W1860005470 @default.
• W2068859969 cites W1968013290 @default.
• W2068859969 cites W1986988638 @default.
• W2068859969 cites W2019612671 @default.
• W2068859969 cites W2019923915 @default.
• W2068859969 cites W2022420133 @default.
• W2068859969 cites W2049783305 @default.
• W2068859969 cites W2053765200 @default.
• W2068859969 cites W2054800029 @default.
• W2068859969 cites W2057103413 @default.
• W2068859969 cites W2066961578 @default.
• W2068859969 cites W2079185127 @default.
• W2068859969 cites W2099605002 @default.
• W2068859969 cites W2107940713 @default.
• W2068859969 cites W2112821460 @default.
• W2068859969 cites W2116365106 @default.
• W2068859969 cites W2117555254 @default.
• W2068859969 cites W2132468746 @default.
• W2068859969 cites W2134243830 @default.
• W2068859969 cites W2143070830 @default.
• W2068859969 cites W2156172044 @default.
• W2068859969 cites W2157843109 @default.
• W2068859969 cites W2160234571 @default.
• W2068859969 cites W2184997735 @default.
• W2068859969 cites W2297853795 @default.
• W2068859969 cites W4234682028 @default.
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