Biology subjects

Gordillo, R.

Publications and source records attributed to Gordillo, R..

7 recordsLinked to original sources

bioRxiv2026

Tyrosine hydroxylase deletion in Ntsr1 neurons confers resistance to diet-induced weight gain: an energy-balance analysis

High-fat diet (HFD) disrupts circadian feeding rhythms and promotes diet-induced obesity (DIO), but the neural mechanisms linking diet to energy balance remain unclear. Previously, we demonstrated that dopamine production in neurotensin receptor 1 (Ntsr1)-expressing neurons was required for HFD-induced daytime overfeeding and DIO. Here, we tested whether DIO resistance in Ntsr1Cre;Thflox conditional knockout (cKO) mice was explained by altered energy expenditure. We replicated resistance to HFD-induced weight gain and assessed food intake, indirect calorimetry, activity, body temperature, fecal energy, fecal nonesterified fatty acids, and the gut microbiome. Indirect calorimetry on standard chow diet (SCD) was confounded by reduced intake and body weight loss, whereas HFD-fed cKO mice consumed food readily and resisted weight gain. Unlike our previous study, daytime feeding was not suppressed; instead, cKO mice were slightly and variably hypophagic on HFD but not SCD. DIO resistance was not accompanied by increased energy expenditure, activity, or body temperature. Rather, cKO mice showed reduced energy expenditure and activity and lower body temperature on both diets. In the replication cohort, HFD fecal output was lower in cKO mice, whereas the independent bomb-calorimetry cohort showed no genotype difference in fecal mass; fecal energy density and nonesterified fatty acid concentration were unchanged. Preliminary analysis of the microbiome was consistent with an obesity-resistant gut profile. Together, these findings indicate that the feeding phenotype is diet- and experiment-dependent and that DIO resistance is not explained by increased energy expenditure, activity, thermogenesis, or detectable changes in fecal energy or fat content.

neuroscience↗

bioRxiv2025

A comparison of adiponectin-deficient mice reveals the fundamental role of intracellular adiponectin

Adiponectin is an important adipokine with insulin-sensitizing, anti-inflammatory, and anti-fibrotic properties. The physiological roles of adiponectin have been studied using global adiponectin knockout (KO) mice. However, the reported phenotypes of adiponectin KO mice vary based on the mouse lines generated by different strategies and investigators. We performed a head-to-head comparison of the adiponectin KO mice that were generated in Dallas, Houston and Osaka. RNAseq revealed that the expression of the bioactive domain of adiponectin - the globular domain - was preserved in the Houston and Osaka KO mice. A complete adiponectin KO model, such as the Dallas KO mouse, exhibits a lower body weight, the highest adipocyte mitochondrial function and displays a susceptibility to DNA damage-mediated lung fibrosis. The reconstitution of globular adiponectin into the Dallas KO mice prompted an increase in body weight and a partial recapitulation of the Osaka KO model transcriptome signature. The intracellular globular adiponectin form is important, as we found that globular adiponectin enhances PPAR{gamma} activity by modulating the coregulators interacting with PPAR{gamma}. Overall, the residual expression of globular adiponectin regulates adipose tissue metabolism by altering PPAR{gamma} activity, highlighting an important novel role of intracellular adiponectin.

physiology↗

bioRxiv2025

A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin

Alpha-ketoglutarate (KG) is required for chromatin demethylation but mechanisms controlling KG abundance in the nucleus are poorly defined. Therefore, we designed a biosensor system to monitor this metabolite pool in human cells using an KG-responsive cyanobacterial transcription factor, NtcA. We then coupled this system with a genetic screen to identify genes that regulate KG in the nucleus, defining an inter-organelle pathway in which sequential mitochondrial activities of the GPT2 transaminase and SLC25A11 transporter supply nuclear KG. Using a mouse model of GPT2 deficiency, a human inborn error of metabolism, we found that this pathway controls chromatin methylation in the developing brain. Our work provides a tool to assess KG signaling to chromatin and a framework for leveraging forward genetics to study nuclear metabolite pools.

synthetic biology↗

bioRxiv2024

Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex

Adipogenin (Adig) is an evolutionarily conserved microprotein and is highly expressed in adipose tissues and testis. Here, we identify Adig as a critical regulator for lipid droplet formation in adipocytes. We determine that Adig interacts directly with seipin, leading to the formation of a rigid complex. We solve the structure of the seipin/Adig complex by Cryo-EM at 2.98[A] overall resolution. Surprisingly, seipin can form two unique oligomers, undecamers and dodecamers. Adig selectively binds to the dodecameric seipin complex. We further find that Adig promotes seipin assembly by stabilizing and bridging adjacent seipin subunits. Functionally, Adig plays a key role in generating lipid droplets in adipocytes. In mice, inducible overexpression of Adig in adipocytes substantially increases fat mass, with enlarged lipid droplets. It also elevates thermogenesis during cold exposure. In contrast, inducible adipocyte-specific Adig knockout mice manifest aberrant lipid droplet formation in brown adipose tissues and impaired cold tolerance.

cell biology↗

bioRxiv2023

Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease

Somatic mutations in non-malignant tissues accumulate with age and insult, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate mutations found in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to non-alcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side-by-side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes identified in human NASH. To prioritize new genes, additional screening of 472 candidates identified 23 somatic perturbations that promoted clonal expansion. In validation studies, liver-wide deletion of Bcl6, Tbx3, or Smyd2 resulted in protection against NASH. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease. HighlightsO_LIMosaic Mboat7 mutations that increase lipotoxicity lead to clonal disappearance in NASH. C_LIO_LIIn vivo screening can identify genes that alter hepatocyte fitness in NASH. C_LIO_LIMosaic Gpam mutations are positively selected due to reduced lipogenesis. C_LIO_LIIn vivo screening of transcription factors and epifactors identified new therapeutic targets in NASH. C_LI

cell biology↗

bioRxiv2021

Adiponectin Preserves Metabolic Fitness During Aging

Adiponectin is essential for the regulation of tissue substrate utilization and systemic insulin sensitivity. Clinical studies have suggested a positive association of circulating adiponectin with healthspan and lifespan. However, the direct effects of adiponectin on promoting healthspan and lifespan remain unexplored. Here, we are using an adiponectin null mouse and a transgenic adiponectin overexpression model. We directly assessed the effects of circulating adiponectin on the aging process and found that adiponectin null mice display exacerbated age-related glucose and lipid metabolism disorders. Moreover, adiponectin null mice have a significantly shortened lifespan on both chow and high-fat diet (HFD). In contrast, a transgenic mouse model with elevated circulating adiponectin levels has a dramatically improved systemic insulin sensitivity, reduced age-related tissue inflammation and fibrosis, and a prolonged healthspan and median lifespan. These results support a role of adiponectin as an essential regulator for healthspan and lifespan.

cell biology↗

bioRxiv2019

Golgi-localized PAQR4 mediates Anti-apoptotic Ceramidase Activity in Breast Cancer

The metabolic network of sphingolipids plays important roles in cancer biology. Prominent sphingolipids include ceramides and sphingosine-1-phosphate that regulate multiple aspects of growth, apoptosis and cellular signaling. Although many significant enzymatic regulators of the sphingolipid pathway have been described in detail, the list is currently incomplete. Here, we applied a systemic approach to identify and molecularly define progestin and adipoQ receptor family member IV (PAQR4) as a Golgi-localized ceramidase. We find PAQR4 to be [~]5 fold upregulated in breast cancer compared to matched control tissue and that its overexpression correlate with disease-specific survival rates in breast cancer. PAQR4 is a seven transmembrane protein, and depletion of PAQR4 leads to cellular apoptosis through accumulation of ceramides. Our findings establish PAQR4 as Golgi-localized ceramidase required for cellular growth in breast cancer.

cancer biology↗