Biology subjects

Yammine, L.

Publications and source records attributed to Yammine, L..

5 recordsLinked to original sources

bioRxiv2026

Do GLP-1 Receptor Agonists Alter Brain Responses to Reward-Related Cues? A Systematic Review

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are approved for treating type 2 diabetes and obesity and are under investigation as potential treatments for substance use disorders (SUD). GLP-1 RA-induced weight loss is thought to arise from both peripheral effects on gastrointestinal function and central modulation of appetite and reward circuits, though the exact mechanisms are unclear. Functional magnetic resonance imaging (fMRI) studies examining brain responses to reward-related cues can help clarify the central mechanisms through which GLP-1 RAs influence reward-seeking behavior. We systematically reviewed the fMRI literature examining how GLP-1 RAs affect brain responses to reward-related cues. We identified 1,209 records through a comprehensive literature search. After screening, only 11 studies met eligibility criteria. The vast majority assessed reactivity to food-related cues, with only one examining drug-related cues (alcohol), leaving neural mechanisms relevant to SUD largely unexplored. None included non-food emotional stimuli as control conditions. Several methodological limitations emerged. Most studies enrolled 20 or fewer participants per group, limiting statistical power. Treatment protocols varied substantially, with some assessing cue responses after single-dose administration and others after chronic treatment. Heterogeneity in medications used further confounds interpretation. The limited evidence tentatively suggests that acute GLP-1 RA administration may reduce brain reactivity to food cues in appetite and reward regions. However, effects appear inconsistent and may attenuate over time. Future studies should recruit larger samples, standardize agents and dosing, and assess responses to diverse motivationally relevant stimuli.

neuroscience↗

bioRxiv2024

Lcn2 protects from cisplatin induced AKI by regulating DNA damage response via EGFR activation

BackgroundLipocalin 2 (Lcn2), a small-secreted protein, is an established sensitive biomarker of kidney injury. In Cisplatin (CDDP) induced acute kidney injury (AKI), Lcn2 expression is swiftly and strongly increased in suffering renal medullary tubules. While recent reports correlates Lcn2 expression in cancer cells with CDDP resistance, the role of Lcn2 in kidney tubule damaged by CDDP remains unknown. MethodsTo better understand the role of Lcn2 in CDDP-induced AKI, experiments on Lcn2+/+ or Lcn2-/- mice as well as immortalized kidney cells knock-down (KD) for Lcn2 were conducted. Kidney function and injury were assessed using standard techniques. Cellular and molecular mechanisms were studied in WT and Lcn2 KD cells in combination with pathways inhibitors in order to gain insight Lcn2 driven mechanisms. ResultsIn animal injected with CDDP, Lcn2 was upregulated mostly in kidney inner medulla collecting duct while it was reabsorbed in the proximal tubules. Lcn2-/- in mice significantly decreased kidney function compare to WT mice, while it increased parenchymal damage due to increased cell death and cast formation. Interestingly, while little to no damage were present in the medulla of CDDP injected WT animal, a clear increase of medulla tubular lesions was observed in Lcn2-/- mice. Using Inner Medullary Collecting Duct cells (mIMDC-3), we showed that Lcn2 KD induces a p53-dependent apoptosis upon Cisplatin exposure while no effect on necrosis was observed. Finally, we demonstrated that Lcn2 drives CDDP resistance to apoptosis through the activation of the pro-survival EGFR pathway. ConclusionsWe established that Lcn2 is a renoprotective protein in CDDP-induced AKI via the activation of EGFR pathway. This new mechanism might represent a new approach for the treatment of AKI.

cell biology↗

bioRxiv2023

GLUT4 dynamic subcellular localization is controlled by AMP kinase activation as revealed by proximal proteome mapping in human muscle cells

Regulation of glucose transport into muscle and adipocytes, central for control of whole-body metabolism, is determined by the amount of GLUT4 glucose transporter in the plasma membrane (PM). Physiologic signals (activated insulin receptor or AMP kinase [AMPK]), acutely increase PM GLUT4 to enhance glucose uptake. Here we show in kinetic studies that intracellular GLUT4 is in equilibrium with the PM in unstimulated cultured human skeletal muscle cells, and that AMPK promotes GLUT4 redistribution to the PM by regulating both exocytosis and endocytosis. AMPK-stimulation of exocytosis requires Rab10 and Rab GTPase activating protein TBC1D4, requirements shared with insulin control of GLUT4 in adipocytes. Using APEX2 proximity mapping, we identify, at high-density and high-resolution, the GLUT4 proximal proteome, revealing GLUT4 traverses both PM proximal and distal compartments in unstimulated muscle cells. These data support intracellular retention of GLUT4 in unstimulated muscle cells by a dynamic mechanism dependent on the rates of internalization and recycling. AMPK promoted GLUT4 translocation to the PM involves redistribution of GLUT4 among the same compartments traversed in unstimulated cells, with a significant redistribution of GLUT4 from the PM distal Trans Golgi Network Golgi compartments. The comprehensive proximal protein mapping provides an integrated, whole cell accounting of GLUT4s localization at a resolution of [~]20 nm, a structural framework for understanding the molecular mechanisms regulating GLUT4 trafficking downstream of different signaling inputs in physiologically relevant cell type and as such, sheds new light on novel key pathways and molecular components as potential therapeutic approaches to modulate muscle glucose uptake.

cell biology↗

bioRxiv2020

Blunting of insulin-stimulated glucose uptake in brown adipose tissue induces systemic metabolic dysregulation in female mice

The role of brown adipose tissue (BAT) in thermogenesis is widely appreciated, whereas its more recently described role in whole-body metabolism is not as well understood. Here we demonstrate that deletion of Rab10 from brown adipocytes reduces insulin-stimulated glucose transport by inhibiting translocation of the GLUT4 glucose transporter to the plasma membrane. This blunting of glucose uptake into brown adipocytes induces glucose intolerance and insulin-resistance in female but not male mice. The defect in glucose uptake does not affect the thermogenic function of BAT, and the dysregulation of whole-body metabolism is independent of the thermogenic function of BAT, thereby revealing a metabolism-specific role for BAT in female mice. The reduced glucose uptake induced by RAB10 deletion disrupts ChREBP regulation of the expression of de novo lipogenesis-related (DNL) genes, providing a link between DNL in BAT and whole-body metabolic regulation that is independent of thermogenesis.

physiology↗

bioRxiv2020

A common human variant of GIPR improves systemic glucose homeostasis in a sexual dimorphic manner

Glucose-dependent insulinotropic polypeptide (GIP) has a role in controlling postprandial metabolic tone. In humans, a GIP receptor (GIPR) variant (Q354, rs1800437) is associated with a lower body mass index (BMI) and increased risk for Type 2 Diabetes. To isolate the contribution of GIPR in metabolic control, we generated a mouse model of the GIPR-Q354 variant (GIPR-Q350 mice). Female GIPR-Q350 mice are leaner than littermate controls, and male GIPR-Q350 mice are resistant to diet-induced obesity, in line with the association of the variant with reduced BMI in humans. GIPR-Q350 mice of both sexes are more glucose tolerant and exhibit an increased sensitivity to GIP. Postprandial GIP levels are reduced in GIPR-Q350 mice, revealing feedback regulation that balances the increased sensitivity of GIP target tissues to secretion of GIP from intestinal endocrine cells. The increased GIP sensitivity is recapitulated ex vivo during glucose stimulated insulin secretion assays in islets. Generation of cAMP in islets downstream of GIPR activation is not affected by the Q354 substitution. However, post-activation traffic of GIPR-Q354 variant in {beta}-cells is altered, characterized by enhanced intracellular dwell time and increased localization to the Trans-Golgi Network (TGN). Consequently, our data link altered intracellular traffic of the GIPR-Q354 variant with GIP control of metabolism. We propose that this change in spatiotemporal signaling underlies the physiologic effects of GIPR-Q350/4 and GIPR-E350/4 in mice and humans. These findings contribute to a more complete understanding of the impact of GIPR-Q354 variant on glucose homeostasis that could perhaps be leveraged to enhance pharmacologic targeting of GIPR for the treatment of metabolic disease.

physiology↗