Biology subjects

Gomez-Banoy, N.

Publications and source records attributed to Gomez-Banoy, N..

5 recordsLinked to original sources

bioRxiv2026

Activation of perivascular thermogenic fat improves aortic stenosis

Aim: Aortic stenosis (AS) is a common condition with exponential increases in incidence in aging populations. Perivascular adipose tissue (PVAT) forms the outer layer of the aortic wall and has - especially in the thoracic area - characteristics of thermogenic adipose tissue, which dissipates energy and releases endocrine factors. Here, we set out to investigate the role of thermogenic PVAT in AS. Methods and results: We studied the role of (PVAT) in the development of AS in a murine model of AS. To specifically delineate the role of PVAT activity in AS, we used a pharmacological {beta}3-adrenergic agonist as well as cold exposure in combination with a genetic mouse model with deficient PVAT development. To investigate the role of thermogenic adipose tissue in human AS, we used 18F-FDG PET-CT imaging. We found that pharmacological activation of thermogenic adipose tissue resulted in an improvement of AS, but not in mice genetically deficient in PVAT. Similarly, PVAT was found to be protective against AS during physiological stimulation of PVAT using cold exposure. Mechanistically, PVAT activation resulted in enhanced aortic distensibility and cellular remodeling of the aortic wall, possibly via release of polyunsaturated fatty acids and oxylipins from perivascular adipocytes. Finally, analysis of thermogenic fat activity in humans revealed that mediastinal thermogenic fat activity correlated negatively with diagnostic criteria of AS severity, suggesting an important role for PVAT activity in human AS. Conclusion: Our data indicate that PVAT activation reduces aortic stenosis and supports aortic remodeling to improve ascending aorta hemodynamics. PVAT activation might be a novel therapeutic target to ameliorate AS progression. Translational perspective: Currently, there are no effective strategies for treating AS other than valve replacement. Since the molecular mechanisms underlying the disease progression remain unclear, there are no pharmacological agents approved for either treatment or prevention of this disease. Furthermore, AS development cannot currently be predicted and is often only diagnosed when patients develop symptoms, which may be 10-20 years after disease onset. Therefore, identifying novel mechanisms that improve aortic valve function and prevent AS is of high medical need. This study identifies activation of PVAT-dependent aortic remodeling as a potential new therapeutic approach to improve or prevent AS.

physiology↗

bioRxiv2026

Cell type-specific proximity labeling of organ secretomes reveals energy balance-dependent proteomic remodeling.

Intercellular communication is critical for maintaining organismal metabolic homeostasis. Here, we present a new method enabling temporally controlled, cell type-specific labeling of secreted and membrane proteins in key metabolic tissues. The method employs a genetically encoded proximity-labeling strategy by targeting a Cre-dependent TurboID ligase to the endoplasmic reticulum (ER) in ES cell-derived mice. Expression of TurboID in liver, adipose tissue, and spleen enabled the characterization of organ-specific ER proteomes at baseline and in response to fasting, inflammation, and dietary obesity, revealing tissue-and perturbation-specific changes and augmenting our understanding of how the proteomes of individual tissues change to regulate systemic energy balance. This comprehensive resource represents an important advance toward understanding both how cell-to-cell communication changes in response to energy homeostasis and how it contributes to these alterations. This method is broadly applicable and provides a means for identifying biomarkers and therapeutic targets across a wide range of tissues.

physiology↗

bioRxiv2025

Ablation of Prdm16 and beige fat causes vascular remodeling and elevated blood pressure

While excess adiposity is a major risk factor for hypertension and cardiovascular disease, brown fat is associated with protection from these pathologies. Whether brown fat has a causal role in this process and the underlying molecular mechanisms remain unknown. Here we investigate the role of murine beige fat, as a model of inducible brown fat in humans, in adipocyte-vascular crosstalk. Using mice with an adipocyte-specific deletion of PRDM16, resulting in a loss of beige adipocyte identity, we discover a dramatic remodeling of perivascular adipose tissue, increased vascular reactivity and elevated blood pressure. We further show that the circulating enzyme Qsox1 is de-repressed in Prdm16-deficient adipocytes, and deletion of Qsox1 in PRDM16cKO mice rescues vascular fibrosis and reactivity. These results demonstrate a key new role for beige adipocytes in blood pressure regulation and identify Qsox1 as an important mediator of adipocyte-vascular crosstalk.

physiology↗

bioRxiv2023

Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome

The canonical G406R gain of function mutation that reduces inactivation and increases Ca2+ influx through the CACNA1C-encoded CaV1.2 voltage gated Ca2+ channel underlies the multisystem disorder Timothy syndrome (TS), characterized by invariant Long QT syndrome and consequent life-threatening arrhythmias. Severe episodic hypoglycemia, which exacerbates arrhythmia risk, is among the myriad non-cardiac TS pathologies that are poorly characterized. While hypoglycemia is thought to result from increased Ca2+ influx through CaV1.2 channels in pancreatic beta cells and consequent hyperinsulinism, this mechanism has never been demonstrated due to a lack of informative animal models, thus hampering development of preventive strategies. We generated a CaV1.2 G406R knockin mouse model that recapitulates key TS features including hypoglycemia. Unexpectedly, these mice did not show hyperactive beta cells or hyperinsulinism in the setting of normal intrinsic beta cell function, suggesting dysregulated glucose homeostasis. We discovered multiple alternative contributors to hypoglycemia, including perturbed counterregulatory hormone responses with defects in glucagon secretion and abnormal hypothalamic glucose sensing. Together, these data provide new insights into physiological contributions of the broadly expressed CaV1.2 channel and reveal integrated consequences of the mutant channel that underlie the life-threatening events in TS. Brief SummaryGain of function mutant CaV1.2 channels drive hypoglycemia through adverse effects on counterregulatory hormones and central nervous system glucose sensing

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↗