Highly Conserved Molecular Features in IgLONs Contrast Their Distinct Structural and Biological Outcomes

Venkannagari, Harikanth; Kasper, James M.; Misra, Abha; Rush, Scott A.; Fan, Shanghua; Lee, Hubert; Sun, Hong; Seshadrinathan, Suchithra; Machius, Mischa; Hommel, Jonathan D.; Rudenko, Gabby

doi:10.1016/j.jmb.2020.07.014

Cited by 19 publications

(19 citation statements)

References 73 publications

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“…NEGR1 in certain hypothalamic nuclei might, therefore, lead to increased appetite, which would be in line with our findings of decreased food consumption in Negr1 −/− mice. These effects may be site-specific, however, as administration of NEGR1 ectodomains into the paraventricular nucleus of the hypothalamus is shown to induce an opposite effect: a 20% decrease in food intake in rats [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Current evidence implies that Negr1 in the hypothalamic area decreases food intake. Higher levels of NEGR1 in hypothalamic nuclei were linked with lower food intake; administration of NEGR1 ectodomains into the paraventricular nucleus of the hypothalamus induced ~20% decrease in food intake in rats [ 23 ]. Negr1 overexpression in the periventricular hypothalamic region, however, did not affect body weight or food intake, whereas knockdown of Negr1 expression in the same nucleus increased body weight [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…In conclusion, accumulating evidence suggests that the systemic effect of Negr1 in the regulation of body weight phenotype might be mediated both by the ability of Negr1 to promote the cell–cell adhesion and neuritogenesis in the hypothalamic area [ 21 , 23 ] and by the independent role of Negr1 in the regulation of fat trafficking/accumulation in peripheral tissues. Walley et al [ 29 ] have shown that there is a high correlation in the expression levels of NEGR1 between human subcutaneous adipose and hypothalamic tissues, suggesting a linked function for NEGR1 across tissues.…”

Section: Introductionmentioning

confidence: 99%

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High-Fat Diet Induces Pre-Diabetes and Distinct Sex-Specific Metabolic Alterations in Negr1-Deficient Mice

et al. 2021

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In the large GWAS studies, NEGR1 gene has been one of the most significant gene loci for body mass phenotype. The purpose of the current study was to clarify the role of NEGR1 in the maintenance of systemic metabolism, including glucose homeostasis, by using both male and female Negr1−/− mice receiving a standard or high fat diet (HFD). We found that 6 weeks of HFD leads to higher levels of blood glucose in Negr1−/− mice. In the glucose tolerance test, HFD induced phenotype difference only in male mice; Negr1−/− male mice displayed altered glucose tolerance, accompanied with upregulation of circulatory branched-chain amino acids (BCAA). The general metabolomic profile indicates that Negr1−/− mice are biased towards glyconeogenesis, fatty acid synthesis, and higher protein catabolism, all of which are amplified by HFD. Negr1 deficiency appears to induce alterations in the efficiency of energy storage; reduced food intake could be an attempt to compensate for the metabolic challenge present in the Negr1−/− males, particularly during the HFD exposure. Our results suggest that the presence of functional Negr1 allows male mice to consume more HFD and prevents the development of glucose intolerance, liver steatosis, and excessive weight gain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High-Fat Diet Induces Pre-Diabetes and Distinct Sex-Specific Metabolic Alterations in Negr1-Deficient Mice

et al. 2021

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“…NEGR1 was reported to be present post-synaptically (Hashimoto et al, 2008) but was also detected in pre-synaptic compartments (Takamori et al, 2006) and was proposed to mediate trans-synaptic adhesion (Ranaivoson et al, 2019; Venkannagari et al, 2020). Hence, we investigated whether pre- or post-synaptic NEGR1 regulates synaptic vesicle recycling by determining the effects of NEGR1 overexpression in axons and dendrites of cultured NEGR1+/+ hypothalamic neurons.…”

Section: Resultsmentioning

confidence: 99%

“…NEGR1 is broadly expressed in the brain (Lee et al, 2012) and accumulates in synapses (Hashimoto et al, 2008; Miyata et al, 2003). NEGR1 molecules bind to each other thereby forming homophilic adhesive bonds connecting synaptic membranes (Miyata et al, 2003; Ranaivoson et al, 2019; Venkannagari et al, 2020). NEGR1 heterophilically interacts with other IgLONs (Miyata et al, 2003; Ranaivoson et al, 2019) and the fibroblast growth factor receptor 2 (FGFR2) (Szczurkowska et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Neuronal growth regulator 1 (NEGR1) promotes synaptic targeting of glutamic acid decarboxylase 65 (GAD65)

Tan

Kozlova

et al. 2022

Preprint

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Neuronal growth regulator 1 (NEGR1) is a glycosylphosphatidylinositol-anchored cell adhesion molecule encoded by an obesity susceptibility gene. We demonstrate that NEGR1 accumulates in GABAergic inhibitory synapses in hypothalamic neurons, a GABA-synthesizing enzyme GAD65 attaches to the plasma membrane, and NEGR1 promotes clustering of GAD65 at the synaptic plasma membrane. GAD65 is removed from the plasma membrane with newly formed vesicles. The association of GAD65 with vesicles results in increased GABA synthesis. In NEGR1 deficient mice, the synaptic targeting of GAD65 is decreased, the GABAergic synapse densities are reduced, and the reinforcing effects of food rewards are blunted. In mice fed a high fat diet, levels of NEGR1 are increased and GAD65 abnormally accumulates at the synaptic plasma membrane. Our results indicate that NEGR1 regulates a previously unknown step required for synaptic targeting and functioning of GAD65, which can be affected by bidirectional changes in NEGR1 levels causing disruptions in the GABAergic signaling controlling feeding behavior.

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Identifying Potential Drug Targets for Keloid: A Mendelian Randomization Study

Wang,

Yuan

et al. 2025

Journal of Investigative Dermatology

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Highly Conserved Molecular Features in IgLONs Contrast Their Distinct Structural and Biological Outcomes

Cited by 19 publications

References 73 publications

High-Fat Diet Induces Pre-Diabetes and Distinct Sex-Specific Metabolic Alterations in Negr1-Deficient Mice

High-Fat Diet Induces Pre-Diabetes and Distinct Sex-Specific Metabolic Alterations in Negr1-Deficient Mice

Neuronal growth regulator 1 (NEGR1) promotes synaptic targeting of glutamic acid decarboxylase 65 (GAD65)

Identifying Potential Drug Targets for Keloid: A Mendelian Randomization Study

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