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Objective: Studies in male mice show that myocardial infarction (MI) leads to the upregulation of type 3 deiodinase (DIO3), the enzyme that inactivates thyroid hormones, which has been regarded as a predictor of poor outcomes after MI. Interestingly, a recent human study has shown a sex-specific regulation of DIO3 after an ischemic event, with women presenting a significant downregulation of this gene. Therefore, this study aims to investigate the biological importance of DIO3 activity on MI recovery in female mice. Methods: Female mice expressing a tamoxifen-inducible Cre-recombinase under the control of the cardiomyocyte-specific Myh6 promoter and carrying a floxed selenocysteine insertion sequence in the DIO3 gene were used to reduce heart DIO3 activity. Animals were treated with tamoxifen (1.5 mg, once daily, for 3 days). MI was induced via ligation of the left anterior descending coronary artery 4 weeks after tamoxifen treatment. Ejection fraction (EF) was measured at baseline, 2 weeks, and 4 weeks after MI induction using echocardiography. Animals were sacrificed 4 weeks post-MI, and heart mitochondrial respiration was measured using Oxygraph-2K. Results: Our data demonstrated that 4 weeks post-MI, females with low DIO3 heart activity show low EF compared to wild-type control mice. We also observed that the cardiac mitochondria of females with low DIO3 activity after MI had lower lipid-linked respiration compared to wild-type control mice. Discussion/Significance of Impact: Impaired cardiomyocyte mitochondrial function has been linked to a reduced ability to recover from MI. We found that lowering cardiac DIO3 activity in female mice caused a reduction in heart function and in cardiomyocyte mitochondrial respiration, suggesting these animals have a reduced ability to recover from MI. The data have important translational implications and clinical significance given that it challenges the current knowledge about DIO3 function after MI and will contribute to explaining why women face a 20% greater risk than men of developing heart failure after MI. Furthermore, it highlights the importance of DIO3 on female heart function since the human DIO3 gene is transcriptionally responsive to estrogen, and MI numbers are relatively low in premenopausal women but significantly increase after menopause. CTSA Grant UL1 TR002535, KL2 TR002534, & TL1 TR002533 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Several discrete groups of feeding-regulated neurons in thenucleus tractus solitarius(NTS) suppress food intake, including aversion-promoting neurons that expressCck(NTSCckcells) and distinctLepr- andCalcr-expressing neurons (NTSLeprand NTSCalcrcells, respectively) that suppress food intake without promoting aversion. To test synergies among these cell groups we manipulated multiple NTS cell populations simultaneously. We found that activating multiple sets of NTS neurons (e.g., NTSLeprplus NTSCalcr(NTSLC), or NTSLCplus NTSCck(NTSLCK)) suppressed feeding more robustly than activating single populations. While activating groups of cells that include NTSCckneurons promoted conditioned taste avoidance (CTA), NTSLCactivation produced no CTA despite abrogating feeding. Thus, the ability to promote CTA formation represents a dominant effect, but activating multiple non-aversive populations additively suppresses food intake without provoking aversion. Although silencing multiple NTS neuron groups augmented food intake and body weight more dramatically than silencing single populations, feeding activated many non-NTSLCKneurons and silencing NTSLCKneurons failed to blunt the weight loss response to vertical sleeve gastrectomy (VSG). Hence, while each of these NTS neuron populations plays crucial and additive roles in the control of energy balance, as-yet undefined cell types must make additional contributions to the control of feeding and the response to VSG.

Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we investigated epigenetic control of systemic metabolism by bromodomain-containing proteins (Brds), which are transcriptional regulators binding to acetylated histone, in both intestinal cells and mice treated with the bromodomain inhibitor JQ-1. In vivo treatment with JQ-1 resulted in hyperglycemia and severe glucose intolerance. Whole-body or tissue-specific insulin sensitivity was not altered by JQ-1; however, JQ-1 treatment reduced insulin secretion during both in vivo glucose tolerance testing and ex vivo incubation of isolated islets. JQ-1 also inhibited expression of fibroblast growth factor (FGF)15 in the ileum and decreased FGF receptor 4-related signaling in the liver. These adverse metabolic effects of Brd4 inhibition were fully reversed by in vivo overexpression of FGF19, with normalization of hyperglycemia. At a cellular level, we demonstrate Brd4 binds to the promoter region of FGF19 in human intestinal cells; Brd inhibition by JQ-1 reduces FGF19 promoter binding and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum and FGF signaling in the liver, and a contributor to the gut-liver axis and systemic glucose metabolism.