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Hea-Jin Jung,
Chika Nobumori,
Chris N Goulbourne,
Yiping Tu,
John M Lee,
Angelica Tatar,
Daniel Wu,
Yuko Yoshinaga,
Pieter J de Jong,
Catherine Coffinier, Loren G Fong,
Stephen G Young
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ABSTRACT: The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left "naked" (free from the nuclear lamina). Thus, farnesylation of lamin B1-but not lamin B2-is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.
Proceedings of the National Academy of Sciences 05/2013; · 9.68 Impact Factor
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ABSTRACT: Members of the lipin protein family are phosphatidate phosphatase (PAP) enzymes, which catalyze the dephosphorylation of phosphatidic acid to diacylglycerol, the penultimate step in TAG synthesis. Lipins are unique among the glycerolipid biosynthetic enzymes in that they also promote fatty acid oxidation through their activity as co-regulators of gene expression by DNA-bound transcription factors. Lipin function has been evolutionarily conserved from a single ortholog in yeast to the mammalian family of three lipin proteins-lipin-1, lipin-2, and lipin-3. In mice and humans, the levels of lipin activity are a determinant of TAG storage in diverse cell types, and humans with deficiency in lipin-1 or lipin-2 have severe metabolic diseases. Recent work has highlighted the complex physiological interactions between members of the lipin protein family, which exhibit both overlapping and unique functions in specific tissues. The analysis of "lipinopathies" in mouse models and in humans has revealed an important role for lipin activity in the regulation of lipid intermediates (phosphatidate and diacylglycerol), which influence fundamental cellular processes including adipocyte and nerve cell differentiation, adipocyte lipolysis, and hepatic insulin signaling. The elucidation of lipin molecular and physiological functions could lead to novel approaches to modulate cellular lipid storage and metabolic disease.
Progress in lipid research 04/2013; · 10.67 Impact Factor
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Claudio J Villanueva,
Laurent Vergnes,
Jiexin Wang,
Brian G Drew,
Cynthia Hong,
Yiping Tu,
Yan Hu,
Xu Peng,
Feng Xu,
Enrique Saez,
Kevin Wroblewski,
Andrea L Hevener,
Karen Reue, Loren G Fong,
Stephen G Young,
Peter Tontonoz
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Claudio J Villanueva,
Laurent Vergnes,
Jiexin Wang,
Brian G Drew,
Cynthia Hong,
Yiping Tu,
Yan Hu,
Xu Peng,
Feng Xu,
Enrique Saez,
Kevin Wroblewski,
Andrea L Hevener,
Karen Reue, Loren G Fong,
Stephen G Young,
Peter Tontonoz
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ABSTRACT: Transcriptional effectors of white adipocyte-selective gene expression have not been described. Here we show that TLE3 is a white-selective cofactor that acts reciprocally with the brown-selective cofactor Prdm16 to specify lipid storage and thermogenic gene programs. Occupancy of TLE3 and Prdm16 on certain promoters is mutually exclusive, due to the ability of TLE3 to disrupt the physical interaction between Prdm16 and PPARγ. When expressed at elevated levels in brown fat, TLE3 counters Prdm16, suppressing brown-selective genes and inducing white-selective genes, resulting in impaired fatty acid oxidation and thermogenesis. Conversely, mice lacking TLE3 in adipose tissue show enhanced thermogenesis in inguinal white adipose depots and are protected from age-dependent deterioration of brown adipose tissue function. Our results suggest that the establishment of distinct adipocyte phenotypes with different capacities for thermogenesis and lipid storage is accomplished in part through the cell-type-selective recruitment of TLE3 or Prdm16 to key adipocyte target genes.
Cell metabolism 03/2013; 17(3):423-35. · 17.35 Impact Factor
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ABSTRACT: A clinical trial of a protein farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here, we discuss the mutation that causes HGPS, the rationale for inhibiting protein farnesyltransferase, the potential limitations of this therapeutic approach, and new potential strategies for treating the disease.
Science translational medicine 02/2013; 5(171):171ps3. · 7.80 Impact Factor
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Elena Scotti,
Martino Calamai,
Chris N Goulbourne,
Li Zhang,
Cynthia Hong,
Ron R Lin,
Jinkuk Choi,
Paul F Pilch, Loren G Fong,
Peng Zou,
Alice Y Ting,
Francesco S Pavone,
Stephen G Young,
Peter Tontonoz
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ABSTRACT: The low-density lipoprotein receptor (LDLR) is a critical determinant of plasma cholesterol levels that internalizes lipoprotein cargo via clathrin-mediated endocytosis. Here we show that the E3 ubiquitin ligase IDOL stimulates a previously unrecognized, clathrin-independent pathway for LDLR internalization. Real-time single particle tracking and electron microscopy reveal that IDOL is recruited to the plasma membrane by LDLR, promotes LDLR internalization in the absence of clathrin or caveolae, and facilitates LDLR degradation by shuttling it into the MVB protein-sorting pathway. The IDOL-dependent degradation pathway is distinct from that mediated by PCSK9, as only IDOL employs ESCRT complexes to recognize and traffic LDLR to lysosomes. siRNA-mediated knockdown of ESCRT0 (HGS) or ESCRT1 (TSG101) components prevents IDOL-mediated LDLR degradation. We further show that USP8 acts downstream of IDOL to deubiquitinate LDLR and that USP8 is required for LDLR entry into the MVB. These results provide key mechanistic insights into an evolutionarily conserved pathway for the control of lipoprotein receptor expression and cellular lipid uptake.
Molecular and cellular biology 02/2013; · 6.06 Impact Factor
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ABSTRACT: The nuclear lamina is an intermediate filament meshwork composed largely of four nuclear lamins - lamins A and C (A-type lamins) and lamins B1 and B2 (B-type lamins). Located immediately adjacent to the inner nuclear membrane, the nuclear lamina provides a structural scaffolding for the cell nucleus. It also interacts with both nuclear membrane proteins and the chromatin and is thought to participate in many important functions within the cell nucleus. Defects in A-type lamins cause cardiomyopathy, muscular dystrophy, peripheral neuropathy, lipodystrophy, and progeroid disorders. In contrast, the only bona fide link between the B-type lamins and human disease is a rare demyelinating disease of the central nervous system - adult-onset autosomal-dominant leukoencephalopathy, caused by a duplication of the gene for lamin B1. However, this leukoencephalopathy is not the only association between the brain and B-type nuclear lamins. Studies of conventional and tissue-specific knockout mice have demonstrated that B-type lamins play essential roles in neuronal migration in the developing brain and in neuronal survival. The importance of A-type lamin expression in the brain is unclear, but it is intriguing that the adult brain preferentially expresses lamin C rather than lamin A, very likely due to microRNA-mediated removal of prelamin A transcripts. Here, we review recent studies on nuclear lamins, focusing on the function and regulation of the nuclear lamins in the central nervous system.
Molecular Neurobiology 10/2012; · 5.74 Impact Factor
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ABSTRACT: Lipoprotein lipase (LPL) is produced by parenchymal cells, mainly adipocytes and myocytes, but is involved in hydrolysing triglycerides in plasma lipoproteins at the capillary lumen. For decades, the mechanism by which LPL reaches its site of action in capillaries was unclear, but this mystery was recently solved. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells, 'picks up' LPL from the interstitial spaces and shuttles it across endothelial cells to the capillary lumen. When GPIHBP1 is absent, LPL is mislocalized to the interstitial spaces, leading to severe hypertriglyceridaemia. Some cases of hypertriglyceridaemia in humans are caused by GPIHBP1 mutations that interfere with the ability of GPIHBP1 to bind to LPL, and some are caused by LPL mutations that impair the ability of LPL to bind to GPIHBP1. Here, we review recent progress in understanding the role of GPIHBP1 in health and disease and discuss some of the remaining unresolved issues regarding the processing of triglyceride-rich lipoproteins. © 2012 The Association for the Publication of the Journal of Internal Medicine.
Journal of Internal Medicine 10/2012; · 5.48 Impact Factor
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Brandon S J Davies,
Chris N Goulbourne,
Richard H Barnes,
Kirsten A Turlo,
Peter Gin,
Sue Vaughan,
David J Vaux,
Andre Bensadoun,
Anne P Beigneux, Loren G Fong,
Stephen G Young
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ABSTRACT: Lipoprotein lipase (LPL) is secreted into the interstitial spaces by adipocytes and myocytes but then must be transported to the capillary lumen by GPIHBP1, a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells. The mechanism by which GPIHBP1 and LPL move across endothelial cells remains unclear. We asked whether the transport of GPIHBP1 and LPL across endothelial cells was uni- or bi-directional. We also asked whether GPIHBP1 and LPL are transported across cells in vesicles and whether this transport process requires caveolin-1. The movement of GPIHBP1 and LPL across cultured endothelial cells was bidirectional. Also, GPIHBP1 moved bidirectionally across capillary endothelial cells in live mice. The transport of LPL across endothelial cells was inhibited by dynasore and genistein, consistent with a vesicular transport process. Also, transmission electron microscopy (EM) and dual-axis EM tomography revealed GPIHBP1 and LPL in invaginations of the plasma membrane and in vesicles. The movement of GPIHBP1 across capillary endothelial cells was efficient in the absence of caveolin-1, and there was no defect in the internalization of LPL by caveolin-1-deficient endothelial cells in culture. Our studies show that GPIHBP1 and LPL move bidirectionally across endothelial cells in vesicles and that transport is efficient even when caveolin-1 is absent.
The Journal of Lipid Research 09/2012; · 5.56 Impact Factor
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ABSTRACT: Inducible degrader of the low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase that mediates the ubiquitination and degradation of the low-density lipoprotein receptor (LDLR). IDOL expression is controlled at the transcriptional level by the cholesterol-sensing nuclear receptor liver X receptor (LXR). In response to rising cellular sterol levels, activated LXR induces IDOL production, thereby limiting further uptake of exogenous cholesterol through the LDLR pathway. The LXR-IDOL-LDLR mechanism for feedback inhibition of cholesterol uptake is independent of and complementary to the sterol regulatory element-binding protein pathway. Since the initial description of the LXR-IDOL pathway, biochemical studies have helped to define the structural basis for both IDOL target recognition and LDLR ubiquitin transfer. Recent work has also suggested links between IDOL and human lipid metabolism.
Arteriosclerosis Thrombosis and Vascular Biology 08/2012; 32(11):2541-6. · 6.37 Impact Factor
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Jennifer R Dwyer,
Jimmy Donkor,
Peixiang Zhang,
Lauren S Csaki,
Laurent Vergnes,
Jessica M Lee,
Jay Dewald,
David N Brindley,
Elisa Atti,
Sotirios Tetradis,
Yuko Yoshinaga,
Pieter J De Jong, Loren G Fong,
Stephen G Young,
Karen Reue
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ABSTRACT: The three lipin phosphatidate phosphatase (PAP) enzymes catalyze a step in glycerolipid biosynthesis, the conversion of phosphatidate to diacylglycerol. Lipin-1 is critical for lipid synthesis and homeostasis in adipose tissue, liver, muscle, and peripheral nerves. Little is known about the physiological role of lipin-2, the predominant lipin protein present in liver and the deficient gene product in the rare disorder Majeed syndrome. By using lipin-2-deficient mice, we uncovered a functional relationship between lipin-1 and lipin-2 that operates in a tissue-specific and age-dependent manner. In liver, lipin-2 deficiency led to a compensatory increase in hepatic lipin-1 protein and elevated PAP activity, which maintained lipid homeostasis under basal conditions, but led to diet-induced hepatic triglyceride accumulation. As lipin-2-deficient mice aged, they developed ataxia and impaired balance. This was associated with the combination of lipin-2 deficiency and an age-dependent reduction in cerebellar lipin-1 levels, resulting in altered cerebellar phospholipid composition. Similar to patients with Majeed syndrome, lipin-2-deficient mice developed anemia, but did not show evidence of osteomyelitis, suggesting that additional environmental or genetic components contribute to the bone abnormalities observed in patients. Combined lipin-1 and lipin-2 deficiency caused embryonic lethality. Our results reveal functional interactions between members of the lipin family in vivo, and a unique role for lipin-2 in central nervous system biology that may be particularly important with advancing age. Additionally, as has been observed in mice and humans with lipin-1 deficiency, the pathophysiology in lipin-2 deficiency is associated with dysregulation of lipid intermediates.
Proceedings of the National Academy of Sciences 08/2012; 109(37):E2486-95. · 9.68 Impact Factor
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ABSTRACT: Lipoprotein lipase (LPL) is a 448-amino-acid head-to-tail dimeric enzyme that hydrolyzes triglycerides within capillaries. LPL is secreted by parenchymal cells into the interstitial spaces; it then binds to GPIHBP1 (glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1) on the basolateral face of endothelial cells and is transported to the capillary lumen. A pair of amino acid substitutions, C418Y and E421K, abolish LPL binding to GPIHBP1, suggesting that the C-terminal portion of LPL is important for GPIHBP1 binding. However, a role for LPL's N terminus has not been excluded, and published evidence has suggested that only full-length homodimers are capable of binding GPIHBP1. Here, we show that LPL's C-terminal domain is sufficient for GPIHBP1 binding. We found, serendipitously, that two LPL missense mutations, G409R and E410V, render LPL susceptible to cleavage at residue 297 (a known furin cleavage site). The C terminus of these mutants (residues 298-448), bound to GPIHBP1 avidly, independent of the N-terminal fragment. We also generated an LPL construct with an in-frame deletion of the N-terminal catalytic domain (residues 50-289); this mutant was secreted but also was cleaved at residue 297. Once again, the C-terminal domain (residues 298-448) bound GPIHBP1 avidly. The binding of the C-terminal fragment to GPIHBP1 was eliminated by C418Y or E421K mutations. After exposure to denaturing conditions, the C-terminal fragment of LPL refolds and binds GPIHBP1 avidly. Thus, the binding of LPL to GPIHBP1 requires only the C-terminal portion of LPL and does not depend on full-length LPL homodimers.
Human Molecular Genetics 04/2012; 21(13):2961-72. · 7.64 Impact Factor
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Sandy Y Chang,
Sarah E Hudon-Miller,
Shao H Yang,
Hea-Jin Jung,
John M Lee,
Emily Farber,
Thangaiah Subramanian,
Douglas A Andres,
H Peter Spielmann,
Christine A Hrycyna,
Stephen G Young, Loren G Fong
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ABSTRACT: Protein farnesyltransferase (FTase) inhibitors, generally called "FTIs," block the farnesylation of prelamin A, inhibiting the biogenesis of mature lamin A and leading to an accumulation of prelamin A within cells. A recent report found that a GGTI, an inhibitor of protein geranylgeranyltransferase-I (GGTase-I), caused an exaggerated accumulation of prelamin A in the presence of low amounts of an FTI. This finding was interpreted as indicating that prelamin A can be alternately prenylated by GGTase-I and that inhibiting both protein prenyltransferases leads to more prelamin A accumulation than blocking FTase alone. Here, we tested an alternative hypothesis-GGTIs are not specific for GGTase-I, and they lead to prelamin A accumulation by inhibiting ZMPSTE24 (a zinc metalloprotease that converts farnesyl-prelamin A to mature lamin A). In our studies, commonly used GGTIs caused prelamin A accumulation in human fibroblasts, but the prelamin A in GGTI-treated cells exhibited a more rapid electrophoretic mobility than prelamin A from FTI-treated cells. The latter finding suggested that the prelamin A in GGTI-treated cells might be farnesylated (which would be consistent with the notion that GGTIs inhibit ZMPSTE24). Indeed, metabolic labeling studies revealed that the prelamin A in GGTI-treated fibroblasts is farnesylated. Moreover, biochemical assays of ZMPSTE24 activity showed that ZMPSTE24 is potently inhibited by a GGTI. Our studies show that GGTIs inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A. Thus, caution is required when interpreting the effects of GGTIs on prelamin A processing.
The Journal of Lipid Research 03/2012; 53(6):1176-82. · 5.56 Impact Factor
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New England Journal of Medicine 03/2012; 366(12):1154-5. · 53.30 Impact Factor
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Hea-Jin Jung,
Catherine Coffinier,
Youngshik Choe,
Anne P Beigneux,
Brandon S J Davies,
Shao H Yang,
Richard H Barnes,
Janet Hong,
Tao Sun,
Samuel J Pleasure,
Stephen G Young, Loren G Fong
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ABSTRACT: Lamins A and C, alternatively spliced products of the LMNA gene, are key components of the nuclear lamina. The two isoforms are found in similar amounts in most tissues, but we observed an unexpected pattern of expression in the brain. Western blot and immunohistochemistry studies showed that lamin C is abundant in the mouse brain, whereas lamin A and its precursor prelamin A are restricted to endothelial cells and meningeal cells and are absent in neurons and glia. Prelamin A transcript levels were low in the brain, but this finding could not be explained by alternative splicing. In lamin A-only knockin mice, where alternative splicing is absent and all the output of the gene is channeled into prelamin A transcripts, large amounts of lamin A were found in peripheral tissues, but there was very little lamin A in the brain. Also, in knockin mice expressing exclusively progerin (a toxic form of prelamin A found in Hutchinson-Gilford progeria syndrome), the levels of progerin in the brain were extremely low. Further studies showed that prelamin A expression, but not lamin C expression, is down-regulated by a brain-specific microRNA, miR-9. Expression of miR-9 in cultured cells reduced lamin A expression, and this effect was abolished when the miR-9-binding site in the prelamin A 3' UTR was mutated. The down-regulation of prelamin A expression in the brain could explain why mouse models of Hutchinson-Gilford progeria syndrome are free of central nervous system pathology.
Proceedings of the National Academy of Sciences 02/2012; 109(7):E423-31. · 9.68 Impact Factor
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ABSTRACT: Protein farnesyltransferase (FTase) and protein geranylgeranyltransferase-I (GGTase-I) add 15- or 20-carbon lipids, respectively, to proteins that terminate with a CaaX motif. These posttranslational modifications of proteins with lipids promote protein interactions with membrane surfaces in cells, but the in vivo importance of the CaaX prenyltransferases and the protein lipidation reactions they catalyze remain incompletely defined. One study concluded that a deficiency of FTase was inconsequential in adult mice and led to little or no tissue pathology. To assess the physiologic importance of the CaaX prenyltransferases, we used conditional knockout alleles and an albumin-Cre transgene to produce mice lacking FTase, GGTase-I, or both enzymes in hepatocytes. The hepatocyte-specific FTase knockout mice survived but exhibited hepatocellular disease and elevated transaminases. Mice lacking GGTase-I not only had elevated transaminases but also had dilated bile cannaliculi, hyperbilirubinemia, hepatosplenomegaly, and reduced survival. Of note, GGTase-I-deficient hepatocytes had a rounded shape and markedly reduced numbers of actin stress fibers. Hepatocyte-specific FTase/GGTase-I double-knockout mice closely resembled mice lacking GGTase-I alone, but the disease was slightly more severe. Our studies refute the notion that FTase is dispensable and demonstrate that GGTase-I is crucial for the vitality of hepatocytes.
The Journal of Lipid Research 01/2012; 53(1):77-86. · 5.56 Impact Factor
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Michael M Weinstein,
Christopher N Goulbourne,
Brandon S J Davies,
Yiping Tu,
Richard H Barnes,
Steven M Watkins,
Ryan Davis,
Karen Reue,
Peter Tontonoz,
Anne P Beigneux, Loren G Fong,
Stephen G Young
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ABSTRACT: Gpihbp1-deficient (Gpihbp1-/-) mice lack the ability to transport lipoprotein lipase to the capillary lumen, resulting in mislocalization of lipoprotein lipase within tissues, defective lipolysis of triglyceride-rich lipoproteins, and chylomicronemia. We asked whether GPIHBP1 deficiency and mislocalization of catalytically active lipoprotein lipase would alter the composition of triglycerides in adipose tissue or perturb the expression of lipid biosynthetic genes. We also asked whether perturbations in adipose tissue composition and gene expression, if they occur, would be accompanied by reciprocal metabolic changes in the liver.
The chylomicronemia in Gpihbp1-/- mice was associated with reduced levels of essential fatty acids in adipose tissue triglycerides and increased expression of lipid biosynthetic genes. The liver exhibited the opposite changes: increased levels of essential fatty acids in triglycerides and reduced expression of lipid biosynthetic genes.
Defective lipolysis in Gpihbp1-/- mice causes reciprocal metabolic perturbations in adipose tissue and liver. In adipose tissue, the essential fatty acid content of triglycerides is reduced and lipid biosynthetic gene expression is increased, whereas the opposite changes occur in the liver.
Arteriosclerosis Thrombosis and Vascular Biology 12/2011; 32(2):230-5. · 6.37 Impact Factor
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Catherine Coffinier,
Hea-Jin Jung,
Chika Nobumori,
Sandy Chang,
Yiping Tu,
Richard H Barnes,
Yuko Yoshinaga,
Pieter J de Jong,
Laurent Vergnes,
Karen Reue, Loren G Fong,
Stephen G Young
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ABSTRACT: Neuronal migration is essential for the development of the mammalian brain. Here, we document severe defects in neuronal migration and reduced numbers of neurons in lamin B1-deficient mice. Lamin B1 deficiency resulted in striking abnormalities in the nuclear shape of cortical neurons; many neurons contained a solitary nuclear bleb and exhibited an asymmetric distribution of lamin B2. In contrast, lamin B2 deficiency led to increased numbers of neurons with elongated nuclei. We used conditional alleles for Lmnb1 and Lmnb2 to create forebrain-specific knockout mice. The forebrain-specific Lmnb1- and Lmnb2-knockout models had a small forebrain with disorganized layering of neurons and nuclear shape abnormalities, similar to abnormalities identified in the conventional knockout mice. A more severe phenotype, complete atrophy of the cortex, was observed in forebrain-specific Lmnb1/Lmnb2 double-knockout mice. This study demonstrates that both lamin B1 and lamin B2 are essential for brain development, with lamin B1 being required for the integrity of the nuclear lamina, and lamin B2 being important for resistance to nuclear elongation in neurons.
Molecular biology of the cell 12/2011; 22(23):4683-93. · 5.98 Impact Factor
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ABSTRACT: We summarize recent progress on GPIHBP1, a molecule that transports lipoprotein lipase (LPL) to the capillary lumen, and discuss several newly studied molecules that appear important for the regulation of LPL activity.
LPL, the enzyme responsible for the lipolytic processing of triglyceride-rich lipoproteins, interacts with multiple proteins and is regulated at multiple levels. Several regulators of LPL activity have been known for years and have been investigated thoroughly, but several have been identified only recently, including an endothelial cell protein that transports LPL to the capillary lumen, a microRNA that reduces LPL transcript levels, a sorting protein that targets LPL for uptake and degradation, and a transcription factor that increases the expression of apolipoproteins that regulate LPL activity.
Proper regulation of LPL is important for controlling the delivery of lipid nutrients to tissues. Recent studies have identified GPIHBP1 as the molecule that transports LPL to the capillary lumen, and have also identified other molecules that are potentially important for regulating LPL activity. These new discoveries open new doors for understanding basic mechanisms of lipolysis and hyperlipidemia.
Current opinion in lipidology 11/2011; 23(1):35-42. · 6.13 Impact Factor
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Parth Patwari,
Valur Emilsson,
Eric E Schadt,
William A Chutkow,
Samuel Lee,
Alessandro Marsili,
Yongzhao Zhang,
Radu Dobrin,
David E Cohen,
P Reed Larsen,
Ann Marie Zavacki, Loren G Fong,
Stephen G Young,
Richard T Lee
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ABSTRACT: A human genome-wide linkage scan for obesity identified a linkage peak on chromosome 5q13-15. Positional cloning revealed an association of a rare haplotype to high body-mass index (BMI) in males but not females. The risk locus contains a single gene, "arrestin domain-containing 3" (ARRDC3), an uncharacterized α-arrestin. Inactivating Arrdc3 in mice led to a striking resistance to obesity, with greater impact on male mice. Mice with decreased ARRDC3 levels were protected from obesity due to increased energy expenditure through increased activity levels and increased thermogenesis of both brown and white adipose tissues. ARRDC3 interacted directly with β-adrenergic receptors, and loss of ARRDC3 increased the response to β-adrenergic stimulation in isolated adipose tissue. These results demonstrate that ARRDC3 is a gender-sensitive regulator of obesity and energy expenditure and reveal a surprising diversity for arrestin family protein functions.
Cell metabolism 11/2011; 14(5):671-83. · 17.35 Impact Factor
