Neural Lazarillo: Biological Overview | References
Gene name - Neural Lazarillo
Cytological map position - 22A1-22A1
Function - transporter of hydrophobic molecules
Symbol - NLaz
FlyBase ID: FBgn0053126
Genetic map position - 2L: 1,359,983..1,361,732 [-]
Classification - Lipocalin / cytosolic fatty-acid binding protein family
Cellular location - secreted
Metabolic homeostasis in metazoans is regulated by endocrine control of insulin/IGF signaling (IIS) activity. Stress and inflammatory signaling pathways -- such as Jun-N-terminal Kinase (JNK) signaling -- repress IIS, curtailing anabolic processes to promote stress tolerance and extend lifespan. While this interaction constitutes an adaptive response that allows managing energy resources under stress conditions, excessive JNK activity in adipose tissue of vertebrates has been found to cause insulin resistance, promoting type II diabetes. Thus, the interaction between JNK and IIS has to be tightly regulated to ensure proper metabolic adaptation to environmental challenges. This study identified a new regulatory mechanism by which JNK influences metabolism systemically. JNK signaling is required for metabolic homeostasis in flies and that this function is mediated by the Drosophila Lipocalin family member Neural Lazarillo (NLaz), a homologue of vertebrate Apolipoprotein D (ApoD) and Retinol Binding Protein 4 (RBP4). Lipocalins are emerging as central regulators of peripheral insulin sensitivity and have been implicated in metabolic diseases. NLaz is transcriptionally regulated by JNK signaling and is required for JNK-mediated stress and starvation tolerance. Loss of NLaz function reduces stress resistance and lifespan, while its over-expression represses growth, promotes stress tolerance and extends lifespan -- phenotypes that are consistent with reduced IIS activity. Accordingly, this study found that NLaz represses IIS activity in larvae and adult flies. The results show that JNK-NLaz signaling antagonizes IIS and is critical for metabolic adaptation of the organism to environmental challenges. The JNK pathway and Lipocalins are structurally and functionally conserved, suggesting that similar interactions represent an evolutionarily conserved system for the control of metabolic homeostasis (Hull-Thompson, 2009).
System-wide coordination of cellular energy consumption and storage is crucial to maintain metabolic homeostasis in multicellular organisms. It is becoming increasingly apparent that endocrine mechanisms that are required for this coordination impact the long-term health of adult animals and significantly influence lifespan and environmental stress tolerance. Insulin/IGF signaling (IIS) is central to this regulation, as loss of Insulin signaling activity impairs metabolic homeostasis, but induces stress tolerance and increases lifespan in a variety of model organisms. Interestingly, environmental stress and cellular damage can systemically repress IIS activity, suggesting the existence of adaptive response mechanisms by which metazoans manage energy resources in times of need. The mechanism(s) and mediators of this endocrine regulatory system are only beginning to be understood (Hull-Thompson, 2009).
Studies in flies and worms have recently identified the stress-responsive Jun-N-terminal Kinase (JNK) signaling pathway as an important component of such an adaptive metabolic response to stress. JNK activation, which can be induced by a variety of environmental stressors, including oxidative stress, represses IIS activity, extending lifespan but limiting growth. Interestingly, similar effects of JNK signaling are also observed in mammals, in which it represses Insulin signal transduction by various mechanisms, including an inhibitory phosphorylation of Ser-307 of the insulin receptor substrate, as well as activation of the transcription factor FoxO. This inhibition contributes to Insulin resistance and the metabolic syndrome in obese mice, suggesting that chronic inflammatory processes (which result in activation of JNK signaling) are central to the etiology of metabolic diseases in obese individuals (Hull-Thompson, 2009).
Endocrine interactions between Insulin-producing and various Insulin-responsive tissues are likely to coordinate the adaptive metabolic response described above. JNK-mediated activation of Foxo in Insulin Producing Cells (IPCs) of flies, for example, represses the expression of insulin-like peptide 2 (dilp2), regulating growth and longevity. At the same time, Foxo activation in the fatbody results in lifespan extension, presumably by an endocrine mechanism that feeds back to IPCs (Hull-Thompson, 2009).
Adipose tissue is increasingly being recognized as an important regulator of metabolic homeostasis. It secretes a variety of so-called adipokines, including the inflammatory cytokine TNF-alpha (Hotamisligil, 2006). TNF-alpha activates JNK signaling, contributing to JNK-mediated insulin resistance in mouse models for obesity. JNK activation in adipose tissue further induces expression of IL-6, which specifically induces Insulin resistance in the liver. While the chronic inhibition of insulin signaling by adipose-derived inflammatory cytokines thus has deleterious effects in obese individuals, it is likely that such endocrine interactions have evolved to govern metabolic homeostasis systemically in an adaptive manner (Hotamisligil, 2006). Supporting this view, adipose tissue is an important regulator of lifespan in worms, flies, and mice, and it is emerging that systemic inhibition of Insulin signaling by adipose-derived factors is involved in this effect (Hull-Thompson, 2009).
An endocrine role for adipose tissue in metabolic regulation has further been demonstrated in mice with adipose-specific deletion of the glucose transporter GLUT4, in which secretion of the Lipocalin family member RBP4 from fat cells induces insulin resistance throughout the organism (Wang, 2005; Abel, 2001; Yang, 2005). Such an endocrine system is expected to be adaptive, since it preserves glucose for only the most essential functions during starvation or environmental stress. At the same time, mis-regulation of this system is likely to contribute to metabolic diseases like type II diabetes. Accordingly, increased serum levels of RBP4 are found in obese and diabetic individuals (Graham, 2006), and polymorphisms in the rbp4 locus are associated with type II diabetes (Munkhtulga, 2006; Hull-Thompson, 2009 and references therein).
The Lipocalins are a large family of mostly secreted proteins that bind small hydrophobic ligands (Flower, 1996; Åkerström, 2006). Lipocalin family members are characterized by a low sequence similarity (reflecting diversification of biological functions), but a highly conserved tertiary protein structure and similar exon/intron structures of their genes (Ganfornina, 2000; Sanchez, 2003). Recent studies implicate various Lipocalins in the regulation of systemic insulin action and of stress responses (Yang, 2005, vanDam, 2007; Yan, 2007; Ganfornina, 2008; Muffat, 2008). Interestingly, the neuroprotective Lipocalin ApoD is strongly induced in aging mice, rhesus macaques and humans, suggesting evolutionarily conserved regulation of this gene, an it induces insulin resistance when overexpressed in the mouse brain (Hull-Thompson, 2009 and references therein).
The Drosophila genome contains three Lipocalin genes: NLaz, GLaz, and karl. Unlike the protein Lazarillo in more ancient insect lineages, which is GPI-anchored to the cell membrane of neurons (Ganfornina, 1995), all Drosophila Lipocalins are secreted extracellular proteins, like ApoD and all other vertebrate Lipocalins. Recent studies have identified an important role for GLaz in stress resistance and lifespan control as well as in the regulation of lipid storage (Walker, 2006; Sanchez, 2006). While the function of NLaz remains unclear, in situ hybridization in Drosophila embryos shows that it is expressed in a subset of neuronal cells, and, interestingly, in the developing fat body (Sanchez, 2006), indicating a potential role in the systemic regulation of metabolism (Hull-Thompson, 2009).
This study shows that NLaz transcription is induced by oxidative stress and by JNK signaling in the fat body, influencing metabolic homeostasis in the fly. Importantly, NLaz induces stress and starvation tolerance downstream of JNK signaling, and negatively regulates Insulin signaling, disrupting glucose homeostasis, repressing growth, and extending lifespan. The results thus indicate that induction of NLaz mediates the antagonistic interaction between JNK and Insulin signaling in flies, acting as part of a stress response mechanism that adjusts metabolism and growth in response to environmental insults (Hull-Thompson, 2009).
The findings support a role for JNK-mediated NLaz induction in the fatbody as a central part of an adaptive endocrine system that coordinates metabolism in response to environmental stress by regulating insulin sensitivity of peripheral tissues. Recent studies have highlighted the role of adipose-derived endocrine factors in such adaptive responses. For example, reducing IIS activity or over-expressing Foxo specifically in adipose tissue leads to lifespan extension and stress tolerance in flies, mice and worms, presumably mediated by systemic repression of IIS. Furthermore, amino acid deprivation of Drosophila fat body cells leads to marked decreases in PI3K activity in wing imaginal discs and in the epidermis. In vertebrates, in contrast, excessive JNK activation in adipose tissue induces insulin resistance in the periphery, promoting Type II diabetes. The current results implicate NLaz as a mediator of such systemic repression of IIS activity by adipose tissue (Hull-Thompson, 2009).
JNK-mediated repression of IIS in flies is thus not only mediated by its function in IPCs, where it represses dilp2 transcription , but also by adipose-specific induction of NLaz, which then inhibits IIS activity in insulin target tissues. This dual antagonism of IIS by JNK is intriguing, as it indicates that adaptive regulation of metabolism requires coordinated control of both insulin-like peptide production and peripheral insulin sensitivity. How the relative contribution of these effects regulates the organism's metabolic homeostasis, stress resistance and lifespan, is an interesting question that will require further investigation (Hull-Thompson, 2009).
Vertebrate Lipocalins have also been implicated in the modulation of insulin action, and recent studies suggest a protective role of these molecules under diverse stress conditions. This function of Lipocalins thus emerges as an evolutionarily conserved adaptive mechanism, and this work integrates this mechanism into the known antagonism between JNK and IIS. Based on the evolutionary conservation of this antagonism it is tempting to speculate that vertebrate Lipocalins also act as effectors of JNK in the regulation of systemic insulin sensitivity, with important implications for potential therapeutic targeting of these molecules (Hull-Thompson, 2009).
While generally promoting metabolic homeostasis and stress tolerance, functional specialization of different Lipocalin family members is expected due to their high sequence divergence. Accordingly, the data show that the Lipocalins present in Drosophila differ in regulation and function. While NLaz and GLaz both regulate stress sensitivity, only NLaz was found to be regulated by JNK signaling. Regulation of Karl, on the other hand, does not influence starvation tolerance (as NLaz does), but promotes resistance against infection by E. faecalis. Further investigation of this diversification of Lipocalin function promises to provide important insight into the systemic regulation of adaptation to diverse environmental challenges. Of particular interest will be to assess the role of Karl as a potential regulator of IIS during infection. Infection with Mycobacterium Marinum can result in significant repression of IIS activity, leading to phenotypes similar to wasting disease. It is intriguing to speculate that excessive JNK-induced Karl expression may cause this pathology (Hull-Thompson, 2009).
In humans, dysregulation of Lipocalins has been correlated with obesity, insulin resistance, and type II diabetes. The cause for this mis-regulation of Lipocalin expression remains unclear, however. The current results implicate JNK signaling, which is activated chronically in obese conditions, as a possible cause. The finding that mammalian lipocalin-2, which impairs insulin action, is induced by the JNK activator TNFalpha, is especially intriguing. Additional studies in vertebrates, as well as in the Drosophila model, will provide further insight into the physiological role of Lipocalins, their regulation by stress signaling, as well as their interaction with Insulin signaling. As Lipocalins are secreted molecules that bind hydrophobic ligands, it is further crucial to identify their physiological ligands in an effort to understand the mechanism(s) by which IIS activity is antagonized by Lipocalins. Such insight promises to provide a deeper understanding of the coordination of metabolic adaptation in metazoans as well as of the etiology of diabetes and other metabolic diseases (Hull-Thompson, 2009).
Apolipoprotein D (ApoD), a member of the Lipocalin family, is the gene most up-regulated with age in the mammalian brain. Its expression strongly correlates with aging-associated neurodegenerative and metabolic diseases. Two homologues of ApoD expressed in the Drosophila brain, Glial Lazarillo (GLaz) and Neural Lazarillo (NLaz), are known to alter longevity in male flies. However, sex differences in the aging process have not been explored so far for these genes. This study demonstrates that NLaz alters lifespan in both sexes, but unexpectedly the lack of GLaz influences longevity in a sex-specific way, reducing longevity in males but not in females. While NLaz has metabolic functions similar to ApoD, the regulation of GLaz expression upon aging is the closest to ApoD in the aging brain. A multivariate analysis of physiological parameters relevant to lifespan modulation uncovers both common and specialized functions for the two Lipocalins, and reveals that changes in protein homeostasis account for the observed sex-specific patterns of longevity. The response to oxidative stress and accumulation of lipid peroxides are among their common functions, while the transcriptional and behavioral response to starvation, the pattern of daily locomotor activity, storage of fat along aging, fertility, and courtship behavior differentiate NLaz from GLaz mutants. Food composition is an important environmental parameter influencing stress resistance and reproductive phenotypes of both Lipocalin mutants. Since ApoD shares many properties with the common ancestor of invertebrate Lipocalins, this global comparison with both GLaz and NLaz should be of use in understanding the complex functions of ApoD in mammalian aging and neurodegeneration (Ruiz, 2011).
This work highlights that the two Drosophila Lipocalins expressed in the nervous system have both functional redundancies and specializations. The response to oxidative stress and accumulation of lipid peroxides are among their common functions, while the transcriptional and behavioral response to starvation, the pattern of daily locomotor activity, storage of fat along aging, fertility, and courtship behavior differentiate NLaz from GLaz mutants. This framework is guiding current research, as more details need to be elucidated. However, it can already be asked how many of these shared or unique functions are conserved in the mammalian homologues also expressed in the brain (Ruiz, 2011).
The basal position of ApoD in the phylogenetic tree of vertebrate Lipocalins suggests that ApoD shares many properties with the common ancestor of invertebrate Lipocalins. However, it has to be taken into account that neither GLaz nor NLaz is a true orthologue of ApoD. Molecular phylogenetic analyses strongly suggest that the Drosophila Lipocalins originated from an independent duplication event, taking place within the invertebrate lineage. Subsequently, the resulting genes have diverged both in their protein coding sequence and their regulatory sequences (Ruiz, 2011).
Since ApoD in the adult mammalian brain is expressed mainly in glial cells, one might be tempted to directly conclude that GLaz is the closest Drosophila homologue. Furthermore, the expression data reported in this study strongly suggest that GLaz regulation through aging is most similar to the robust increase of mammalian ApoD in the aged brain (de Magalhaes; Loerch, 2008). Interestingly, ApoD is most similar to GLaz in protein sequence, but to NLaz in the intron-exon structure of the gene. ApoD has been shown to be up-regulated by oxidative stress in astrocytes, and this induction is mediated through the JNK pathway (Bajo-Grañeras, Ganfornina and Sanchez, unpublished observations cited in Ruiz, 2011), comparable to the NLaz JNK-mediated induction by stress in Drosophila. Thus, if the Drosophila data is extrapolated to learn about the functions of ApoD in mammalian aging and neurodegeneration the global comparison with both GLaz and NLaz, as reported in this study, must be taken into account (Ruiz, 2011).
To understand the multigenic control of aging, it must be taken into account that a layer of complexity is added due to the fact that each gene has pleiotropic effects, and each one has differing degrees of specialization or redundancy with members of the same gene family. This fact represents a daunting complication for the task of predicting the actions of putative anti-aging or anti-neurodegeneration drugs. However, complexity should not prevent investigating until a comprehensive understanding of the aging process is available (Ruiz, 2011).
In multicellular organisms, insulin/IGF signaling (IIS) plays a central role in matching energy needs with uptake and storage, participating in functions as diverse as metabolic homeostasis, growth, reproduction and ageing. In mammals, this pleiotropy of action relies in part on a dichotomy of action of insulin, IGF-I and their respective membrane-bound receptors. In organisms with simpler IIS, this functional separation is questionable. In Drosophila IIS consists of several insulin-like peptides called Dilps, activating a unique membrane receptor and its downstream signaling cascade. During larval development, IIS is involved in metabolic homeostasis and growth. This study has used feeding conditions (high sugar diet, HSD) that induce an important change in metabolic homeostasis to monitor possible effects on growth. Unexpectedly it was observed that HSD-fed animals exhibited severe growth inhibition as a consequence of peripheral Dilp resistance. Dilp-resistant animals present several metabolic disorders similar to those observed in type II diabetes (T2D) patients. By exploring the molecular mechanisms involved in Drosophila Dilp resistance, a major role was found for the lipocalin Neural Lazarillo (NLaz), a target of JNK signaling. NLaz expression is strongly increased upon HSD and animals heterozygous for an NLaz null mutation are fully protected from HSD-induced Dilp resistance. NLaz is a secreted protein homologous to the Retinol-Binding Protein 4 involved in the onset of T2D in human and mice. These results indicate that insulin resistance shares common molecular mechanisms in flies and human and that Drosophila could emerge as a powerful genetic system to study some aspects of this complex syndrome (Pasco, 2012).
One particularity of the insect IIS is the presence of a unique receptor for multiple insulin-like peptides. This raises the possibility that the multiple functions assigned to IIS might not be independently regulated following an acute variation in environmental conditions (the 'coupling hypothesis'). This was tested experimentally during larval development, where IIS controls both systemic growth and carbohydrate homeostasis. Previous results showed that a limitation in dietary amino acids reduces circulating Dilps, which impacts both growth and carbohydrate homeostasis. This study used experimental conditions where carbohydrate metabolism is challenged by a high sugar diet and its effect on growth is monitored. HSD induced an increase in glycemia followed by increased insulinemia (high Dilp expression and accumulation in the IPCs, elevated Dilp2 concentrations in the hemolymph), which was anticipated to induce overgrowth. In contrast, HSD fed larvae gave rise to small flies due to Dilp resistance in peripheral tissue. This indicates that Dilp resistance in flies impacts both metabolic and growth functions. This raises the possibility that Dilps and IIS are not used to maintain glucose homeostasis in normal physiological conditions. Previous work has demonstrated that the fly glucagon AKH has a selective action on carbohydrate and lipid homeostasis without influencing growth. Therefore, using AKH and not Dilps to control energy homeostasis would prevent larvae from accidental coupling between metabolism and growth. This possibility finds support in the fact that AKH cells, but not Dilp cells, couple secretion to variations in glucose and internal ATP levels. The current experiments did not did not reveal noticeable changes in AKH expression or accumulation in the AKH-producing cells in response to HSD. Moreover, there is strong experimental evidence that, in addition to their growth-promoting function, circulating Dilps can influence metabolic homeostasis. This overall indicates that despite a conservation of its multiple functional outputs, the hard wiring of IIS in Drosophila does not allow a clear discrimination of growth and metabolic regulations during larval development. What are the respective contributions of Dilps and AKH to energy homeostasis in the adult fly are questions awaiting further investigation (Pasco, 2012).
In human studies, the link between dietary carbohydrates and the development of insulin resistance and type II diabetes has long been elusive, mainly because of the difficulty to evaluate glycemic loads and indexes from food questionnaires. An increasing number of epidemiological studies now point to a role of carbohydrates in the emergence of T2D in human. In this study, in less than four days of feeding on HSD, larval tissues become strongly resistant to the effect of Dilps in vivo and to human insulin ex-vivo. This insulin-resistant state is characterized by: (1) high glycemia despite increased insulinemia, (2) increased lipid storage and circulating lipids, (3) rescue by forced Dilps secretion, (4) lack of response of peripheral tissues to stimulation by exogenous insulin. This last point was tested in different larval tissues including the fat body, which carries both hepatic and adipose functions in the larva. HSD-fed animals accumulate high lipid levels in the fat body, which becomes resistant to the action of exogenous insulin. This is reminiscent of metabolic alterations seen in response to over-nutrition in mammals, where lipid metabolites accumulate in the liver leading to liver steatosis, a hallmark of insulin resistance and T2D. In line with this, it was found that ACC expression is strongly increased in the fat body of HSD-fed larvae. This enzyme transforms acetyl-CoA into malonyl-CoA, a precursor for lipogenesis and an inhibitor of CPT-1, which imports long chain acyl CoA in the mitochondria for beta-oxydation. Suppression of ACC2 activity in mice induces beta-oxidation and was shown sufficient to reverse hepatic insulin resistance. Therefore, the fat body of HSD-fed animals is subjected to metabolic alterations similar to those taking place in the fatty liver of T2D or obese patients. These observations parallel those of Musselman (2011) who recently published a state of sugar-induced insulin resistance in Drosophila (Pasco, 2012).
One striking finding is the fact that heterozygous NLaz/+ animals are fully protected of insulin resistance when exposed to a HSD. NLaz is a Drosophila lipocalin that is strongly up-regulated upon HSD feeding. NLaz was previously shown to act downstream of JNK to maintain metabolic homeostasis, in part by controlling lipid biogenesis and circulating carbohydrate levels. NLaz expression in the larval fat body reduces general IIS levels, whereas NLaz mutant larvae present elevated IIS. It was also found that silencing NLaz in fat cells protects larvae from HSD-induced Dilp resistance. The role of NLaz as a potential adipokine antagonizing IIS for metabolic regulation is remarkably similar to the role of its mammalian orthologs, Lipocalin 2 and the Retinol-Binding Protein 4 (RBP4). Serum concentration of both lipocalins correlate with obesity, T2D and insulin resistance in human and mice, although some of these associations have been disputed in human patients in the case of RBP4. The reduction of RBP4 concentration in diet-induced obese mice was shown to improve insulin sensitivity whereas injection of recombinant RBP4 decreases insulin sensitivity in normal mice, a phenotype associated with a strong induction of the neoglucogenic enzyme PEPCK (Yang, 2005). In addition, a functional polymorphism in the RBP4 gene associated with increased serum RBP4 was found in a Mongolian population suffering rapid increase of diabetes. These observations are functionally related to the present findings in Drosophila showing that heterozygosity for NLaz is sufficient to protect animals from diet-induced insulin resistance. In addition, the level of expression of the Drosophila PEPCK gene is strongly reduced in Nlaz mutant animals, even if ectopic expression of Nlaz is not sufficient to drive PEPCK expression (a result in line with the absence of PEPCK induction upon HSD). These data collectively suggest a common molecular basis for the mechanism of insulin resistance in organisms as distant as insects and mammals. Further work using both vertebrate and invertebrate models should help understand the role of circulating lipocalins in reducing insulin sensitivity in peripheral tissues (Pasco, 2012).
In summary, the present study recapitulates in a highly genetically amenable system some of the interactions observed between genetic factors and environmental factors leading to T2D as pinpointed by epidemiological studies in patients. This is the demonstration that the fly can be used to screen for genes that predispose to insulin resistance with conserved functions in mammals. The clinical progression towards TD2 is still not well understood and the use of genetic models might prove useful to decipher some of its underlying mechanisms (Pasco, 2012).
Search PubMed for articles about Drosophila Neural Lazarillo
Abel, E. D., et al. (2001). Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409: 729-733. PubMed ID: 11217863
Åkerström, B., Borregaard, N., Flower, D. R. and Salier, J. P. (2006). Austin, TX: Lipocalins, Landes Bioscience.
de Magalhaes, J. P. Curado, J. and Church, G. M. (2009). Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25: 875-881. PubMed ID: 19189975
Flower, D. R. (1996). The lipocalin protein family: structure and function. Biochem J. 318 (Pt 1): 1-14. PubMed ID: 8761444
Ganfornina, M. D., Sanchez, D. and Bastiani, M. J. (1995). Lazarillo, a new GPI-linked surface lipocalin, is restricted to a subset of neurons in the grasshopper embryo. Development 121: 123-134. PubMed ID: 7867494
Ganfornina, M. D., Gutierrez, G., Bastiani, M. and Sanchez, D. (2000). A phylogenetic analysis of the lipocalin protein family. Mol. Biol. Evol. 17: 114-126. PubMed ID: 10666711
Ganfornina, M. D., et al. (2008). Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress. Aging Cell 7(4): 506-15. PubMed ID: 18419796
Graham, T. E., et al. (2006). Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N. Engl. J. Med. 354: 2552-2563. PubMed ID: 16775236
Hotamisligil, G. S. (2006). Inflammation and metabolic disorders. Nature 444: 860-867. PubMed ID: 17167474
Hull-Thompson, J., Muffat, J., Sanchez, D., Walker, D. W., Benzer, S., Ganfornina, M. D. and Jasper, H. (2009). Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz. PLoS Genet. 5(4): e1000460. PubMed ID: 19390610
Loerch, P. M., et al. Evolution of the aging brain transcriptome and synaptic regulation, PLoS ONE 3: e3329. PubMed ID: 18830410
Muffat, J., Walker, D. W. and Benzer, S. (2008). Human ApoD, an apolipoprotein up-regulated in neurodegenerative diseases, extends lifespan and increases stress resistance in Drosophila. Proc. Natl. Acad. Sci. 105: 7088-7093. PubMed ID: 18458334
Munkhtulga, L., et al. (2006). Identification of a regulatory SNP in the retinol binding protein 4 gene associated with type 2 diabetes in Mongolia. Hum Genet. 120(6): 879-88. PubMed ID: 17006670
Musselman, L. P., Fink, J. L., Narzinski, K., Ramachandran, P. V., Hathiramani, S. S., Cagan, R. L. and Baranski, T. J. (2011). A high-sugar diet produces obesity and insulin resistance in wild-type Drosophila. Dis Model Mech 4: 842-849. Pubmed: 21719444
Pasco, M. Y. and Leopold, P. (2012). High sugar-induced insulin resistance in Drosophila relies on the lipocalin Neural Lazarillo. PLoS One 7: e36583. Pubmed: 22567167
Ruiz, M., Sanchez, D., Canal, I., Acebes, A. and Ganfornina, M. D. (2011). Sex-dependent modulation of longevity by two Drosophila homologues of human Apolipoprotein D, GLaz and NLaz. Exp. Gerontol. 46(7): 579-89. PubMed ID: 21376794
Sanchez, D., Ganfornina, M. D., Gutierrez, G. and Marin, A. (2003). Exon-intron structure and evolution of the Lipocalin gene family. Mol. Biol. Evol. 20: 775-783. PubMed ID: 12679526
Sanchez, D., et al. (2006). Loss of glial lazarillo, a homolog of apolipoprotein D, reduces lifespan and stress resistance in Drosophila. Curr. Biol. 16: 680-686. PubMed ID: 16581513
van Dam, R. M. and Hu, F. B. (2007). Lipocalins and insulin resistance: etiological role of retinol-binding protein 4 and lipocalin-2? Clin Chem 53: 5-7. PubMed ID: 17202496
Walker, D. W., Muffat, J., Rundel, C. and Benzer, S. (2006). Overexpression of a Drosophila homolog of apolipoprotein D leads to increased stress resistance and extended lifespan. Curr. Biol. 16: 674-679. PubMed ID: 16581512
Wang, M. C., Bohmann, D. and Jasper, H. (2005). JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell 121: 115-125. PubMed ID: 15820683
Yan, Q. W., et al. (2007). The adipokine lipocalin 2 is regulated by obesity and promotes insulin resistance. Diabetes 56: 2533-2540. PubMed ID: 17639021
Yang, Q., Graham, T. E., Mody, N., Preitner, F., Peroni, O. D., Zabolotny, J. M., Kotani, K., Quadro, L. and Kahn, B. B. (2005). Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436: 356-362. Pubmed: 16034410
date revised: 12 April 2022
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