Biology subjects

Inouye, K. E.

Publications and source records attributed to Inouye, K. E..

5 recordsLinked to original sources

bioRxiv2024

An Adipo-Pulmonary Axis Mediated by FABP4 Hormone Defines a Therapeutic Target Against Obesity-Induced Airway Disease

Obesity-related airway disease is a clinical condition without a clear description and effective treatment. Here, we define this pathology and its unique properties, which differ from classic asthma phenotypes, and identify a novel adipo-pulmonary axis mediated by FABP4 hormone as a critical mediator of obesity-induced airway disease. Through detailed analysis of murine models and human samples, we elucidate the dysregulated lipid metabolism and immunometabolic responses within obese lungs, particularly highlighting the stress response activation and downregulation of surfactant-related genes, notably SftpC. We demonstrate that FABP4 deficiency mitigates these alterations, demonstrating a key role in obesity-induced airway disease pathogenesis. Importantly, we identify adipose tissue as the source of FABP4 hormone in the bronchoalveolar space and describe strong regulation in the context of human obesity, particularly among women. Finally, our exploration of antibody-mediated targeting of circulating FABP4 unveils a novel therapeutic avenue, addressing a pressing unmet need in managing obesity-related airway disease. These findings not only define the presence of a critical adipo-pulmonary endocrine link but also present FABP4 as a therapeutic target for managing this unique airway disease that we refer to as fatty lung disease associated with obesity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=162 HEIGHT=200 SRC="FIGDIR/small/603433v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@c1449corg.highwire.dtl.DTLVardef@7f6869org.highwire.dtl.DTLVardef@9fd41corg.highwire.dtl.DTLVardef@11eb408_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryInvestigating FABP4s pivotal role in obesity-driven airway disease, this study unveils an adipo-pulmonary axis with potential therapeutic implications.

physiology↗

bioRxiv2024

An Organism-Level Quantitative Flux Model of Mammalian Energy Metabolism

Mammalian tissues feed on nutrients in the blood circulation. At the organism-level, mammalian energy metabolism comprises of oxidation, storage, interconverting, and releasing of circulating nutrients. Though much is known about the individual processes and nutrients, a holistic and quantitative model describing these processes for all major circulating nutrients is lacking. Here, by integrating isotope tracer infusion, mass spectrometry, and isotope gas analyzer measurement, we developed a framework to systematically quantify fluxes through these metabolic processes for 10 major circulating energy nutrients in mice, resulting in an organism-level quantitative flux model of energy metabolism. This model revealed in wildtype mice that circulating nutrients have more dominant metabolic cycling fluxes than their oxidation fluxes, with distinct partition between cycling and oxidation flux for individual circulating nutrients. Applications of this framework in obese mouse models showed on a per animal basis extensive elevation of metabolic cycling fluxes in ob/ob mice, but not in diet-induced obese mice. Thus, our framework describes quantitatively the functioning of energy metabolism at the organism-level, valuable for revealing new features of energy metabolism in physiological and disease conditions. HighlightsO_LIA flux model of energy metabolism integrating 13C labeling of metabolites and CO2 C_LIO_LICirculating nutrients have characteristic partition between oxidation and storage C_LIO_LICirculating nutrients total cycling flux outweighs their total oxidation flux C_LIO_LICycling fluxes are extensively elevated in ob/ob but not in diet-induced obese mice C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/579776v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@2175c4org.highwire.dtl.DTLVardef@ba96edorg.highwire.dtl.DTLVardef@aac3corg.highwire.dtl.DTLVardef@b1cb7a_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2023

Ubiquinone deficiency drives reverse electron transport to disrupt hepatic metabolic homeostasis in obesity

Mitochondrial reactive oxygen species (mROS) are central to physiology. While excess mROS production has been associated with several disease states, its precise sources, regulation, and mechanism of generation in vivo remain unknown, limiting translational efforts. Here we show that in obesity, hepatic ubiquinone (Q) synthesis is impaired, which raises the QH2/Q ratio, driving excessive mROS production via reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo we demonstrated that RET is critical for metabolic health. In patients with steatosis, the hepatic Q biosynthetic program is also suppressed, and the QH2/Q ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.

biochemistry↗

bioRxiv2022

Endothelial FABP4 constitutes the majority of basal circulating hormone levels and regulates lipolysis-driven insulin secretion

Fatty acid binding protein 4 (FABP4) is a lipid chaperone secreted from adipocytes upon stimulation of lipolysis. Circulating FABP4 levels strongly correlate with body mass index and obesity-related pathologies in experimental models and humans. While adipocytes have been presumed to be the major source of hormonal FABP4, this question has not been addressed definitively in vivo. We generated mice with FABP4 deletion in cells known to express the gene; adipocytes (Adipo-KO), endothelial cells (Endo-KO), myeloid cells (Myeloid-KO), and the whole body (Total-KO) to examine the contribution of these cell types to basal and stimulated plasma FABP4 levels. Unexpectedly, baseline plasma FABP4 was only reduced by [~]25% in Adipo-KO mice, whereas Endo-KO mice showed [~]75% decreases compared to wildtype controls. In contrast, Adipo-KO mice exhibited [~]62% reduction in FABP4 responses to lipolysis, while there was minimal reduction in Endo-KO mice, indicating that adipocytes are the main FABP4 source in lipolysis. We did not detect any myeloid cell contribution to circulating FABP4. Surprisingly, despite the nearly intact FABP4 responses, Endo-KO mice showed blunted lipolysis-induced insulin secretion, identical to Total-KO mice. We conclude that the endothelium is the major source of baseline hormonal FABP4 and is required for the insulin response to lipolysis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/511807v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1b2d566org.highwire.dtl.DTLVardef@1d82083org.highwire.dtl.DTLVardef@3e9726org.highwire.dtl.DTLVardef@1357648_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

ATGL is differentially required for adipocyte FABP4 secretion in vivo and ex vivo

Fatty acid binding protein 4 (FABP4) is linked with the pathogenesis of metabolic diseases, including diabetes and cardiovascular disease in both mice and humans. It has also been demonstrated that the levels of hormonal FABP4 are strongly associated with obesity, and secretion is stimulated under conditions of fasting and lipolysis both in vivo and in vitro. Here, we utilized adipocyte-specific deficiency of adipose triglyceride lipase (ATGL) in a mouse model (ATGLAdpKO) to evaluate the regulation of FABP4 secretion by lipolytic signals in the absence of actual lipolysis in vivo. Previously, lipolysis-induced FABP4 secretion was found to be significantly reduced upon pharmacological inhibition of ATGL, and from adipose tissue explants from ATGLAdpKO mice. Unexpectedly, upon activation beta-adrenergic receptors, ATGLAdpKO mice exhibited significantly higher levels of circulating FABP4 as compared to ATGLfl/fl controls in vivo, with no corresponding increase in non-esterified free fatty acids or glycerol, confirming the lack of lipolysis. We also generated an additional model with adipocyte-specific deletion of FABP4 in the background of ATGLAdpKO mice (ATGL/FABP4AdpKO or DKO) to evaluate the cellular source of circulating FABP4. In these animals, there was no evidence of lipolysis-induced FABP4 secretion, indicating that the elevated FABP4 hormone levels in the ATGLAdpKO mice were indeed from the adipocytes. ATGLAdpKO mice did not exhibit an increase in insulin secretion upon stimulation of lipolysis, but had a normal insulin response to glucose injection along with increased FABP4 secretion, suggesting the elevated FABP4 secretion is not due to lack of insulin. Inhibition of sympathetic signaling during lipolysis using hexamethonium significantly reduced FABP4 secretion in ATGLAdpKO mice compared to controls. Therefore, activity of a key enzymatic step of lipolysis mediated by ATGL, per se, is not required for stimulated in vivo FABP4 secretion from adipocytes, which can be induced through sympathetic signaling.

physiology↗