Biology subjects

Kotikalapudi, N.

Publications and source records attributed to Kotikalapudi, N..

4 recordsLinked to original sources

bioRxiv2026

GDF3 is an endogenous antagonist of the ActE-ALK7/ACVR2 pathway in adipocytes

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) arise, in part, from excessive free fatty acid flux from adipose tissue to the liver. Activin E (ActE, encoded by INHBE) suppresses adipocyte lipolysis through the type I receptor ALK7 (ACVR1C). Loss-of-function variants in INHBE and ACVR1C reduce waist-to-hip ratio in humans, yet genetic knockouts in mice produce insulin resistance and hepatic steatosis, suggesting discrepancies between human and mouse biology. We identify GDF3, a TGF-{beta} superfamily ligand upregulated in obese adipose tissue, as the principal endogenous antagonist of ActE/ALK7 signaling. Human transcriptomic datasets reveal coordinated dysregulation: hepatic INHBE expression and circulating ActE protein are elevated in obesity, while adipose ACVR1C is downregulated and GDF3 is reciprocally upregulated. Using ALK7-selective reporter assays, we show GDF3 inhibits ActE-driven SMAD2/3 signaling as a competitive antagonist rather than the weak agonist previously proposed. ActE suppressed beta-adrenergic-stimulated lipolysis in mouse and human adipocytes and primary human adipose tissue; GDF3 overexpression abolished this effect. In diet-induced obese mice, inducible Gdf3 deletion reduced adipose lipolysis, resolved hepatic steatosis and fibrosis, and improved insulin sensitivity, benefits abolished by Inhbe knockdown, confirming dependence on ActE signaling. Predicted loss-of-function variants in INHBE show only nominal, WHR-dependent associations with type 2 diabetes risk, potentially confounded by hematological effects on HbA1c. Gdf3 deficiency synergized with the clinical-stage anti-activin receptor antibody Bimagrumab to amplify fat-mass loss and improve glucose homeostasis in multiple MASH models. These findings establish GDF3 as an endogenous antagonist of ActE-ALK7 signaling and nominate GDF3 inhibition as a therapeutic strategy for MASLD/MASH.

physiology↗

bioRxiv2026

A Course-Undergraduate Research Experience (CURE) to explore the effect of structural variants on gene expression in C. elegans balancers

Bioinformatics, a discipline at the crossroads of Biology and Computational Sciences, also referred to as Computational Biology, is nowadays widely spread in research programs. However, implementing any Bioinformatics projects requires the ability to comprehend biological concepts and apply computational approaches, and rare are the undergraduate programs offering such multi-disciplinary training. In addition, understanding the dynamic between Biology research projects and Bioinformatics analyses is challenging with no real-life experience. Course-based undergraduate research experience (CURE) courses are innovative programs that allow more students to acquire research experience and provide the perfect setting to introduce students to applied bioinformatics. As a part of the Bachelor of Health Sciences of the Cumming School of Medicine at the University of Calgary (Canada), a CURE applied bioinformatics was implemented in the Winter of 2023 to 2025. Students investigated the effect of structural variants (SVs, genetic variants larger than 50 bp) on gene expression in the model organism Caenorhabditis elegans (a hermaphrodite 1-mm long roundworm). The students detected and characterized SVs by analyzing genome and transcriptome sequencing data of C. elegans strains called balancers, as they are known to carry large genomic variations balancing regions of the genome by limiting recombination and allowing maintenance of lethal mutations. They used Galaxy, a public web-based supercomputing resource, but also a local High-Performance computing system, and R, to report different effects of SVs on gene expression and splicing. Students research explained the molecular mechanism behind the uncoordinated phenotype caused by the reciprocal translocation eT1(III;V) and uncovered unexpected effects on gene expression on an understudied gene. We evaluated the courses impact on student learning journeys and showed that the CURE favored students understanding of the Bioinformatics field and fostered their research interest. We provide here guidelines to facilitate the CURE implementations to improve access for undergraduate students to bioinformatics research experiences.

bioinformatics↗

bioRxiv2025

Microbial metabolism of mannitol as a tracer for the non-invasive measurement of oral-cecal transit

The timing of digestion after a meal reveals information essential for evaluating gastrointestinal function and overall digestive health. Alterations in transit time through the GI tract can reveal abnormalities such as delayed gastric emptying and provide critical insights into nutrient absorption dynamics. This information is particularly valuable for optimizing dietary interventions, managing metabolic conditions such as diabetes, and improving personalized nutrition strategies. Methods for measuring the oral to cecal transit time (OCTT) in murine models have significant limitations. We demonstrate a non-invasive approach in freely-moving non-anesthetized mice which quantifies the microbial digestion of the non-nutritive sweetener mannitol to CO2. We monitor cage air for the production of 13CO2 from 13C-enriched mannitol using Off-Axis Integrated Cavity Output Spectroscopy integrated with multiplexes indirect calorimetry. With this approach, we find mannitol oxidation is absent in mice following commensal depletion of the microbiota. In mice with conventional microbiota, the peak 13C-mannitol oxidation occurs proximal to the mouse cecum, allowing the quantitation of OCTT in mice. By tracking the output of 13CO2, this method provides highly granular, real-time data. We detect delayed OCTT with the use of pharmacological transit-altering compounds loperamide, a gut restricted opioid receptor agonist and also semaglutide, a GLP-1 receptor agonist. This approach may provide more physiologically relevant results in a range of genetic, environmental, and pharmacological research models.

physiology↗

bioRxiv2022

GDF3 simultaneously antagonizes BMP signaling and activates TGFβ receptor signaling

Growth differentiation factor 3 (GDF3) is a relatively understudied member of the TGF{beta} superfamily that is highly expressed during development. However, the function of GDF3 in adult biology is contentious. We use in vivo approaches to show that GDF3 loss-of-function in adipose tissue of obese adult mice causes reduced body weight and improved whole-body insulin sensitivity. These effects are accompanied by altered regulation of genes targeted by the TGF{beta} superfamily in vivo. Using in vitro approaches, we show that GDF3 can influence both arms of the TGF{beta} superfamily: GDF3 simultaneously inhibits BMP signaling and activates activin-like SMAD 2/3 signaling. We identify the type II receptors mediating this activity. GDF3 binds to the type II receptors BMPR2, ACTRIIA and ACTRIIB and achieves dose-dependent inhibition of multiple BMP proteins including BMP2, BMP7, BMP9, BMP10, and BMP15 in vitro. We also find that GDF3 activates TGF{beta}/activin-like SMAD2/3 signaling. Unbiased expression profiling confirms that GDF3 both attenuates BMP2-regulated gene expression and drives TGF{beta}/activin-like gene expression. Together these results provide much needed clarity to both the molecular pathways involved in GDF3 signaling and the physiological effects of GDF3 loss of function.

cell biology↗