Browsing by Author "Huang, Carol T. L."

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    Developmental Adipogenesis and Later-Life Cardiometabolic Risk in Offspring Exposed to Dams with Metabolic Dysfunction
    (2020-09-25) Mikolajczak, Anna; Thompson, Jennifer A.; Huang, Carol T. L.; Slater, Donna M.
    Intrauterine exposure to maternal obesity and diabetes is linked to the development of obesity and other cardiovascular disease (CVD) risk factors in the offspring. The hypothesis for this study is that impaired subcutaneous adipose tissue (SAT) expandability underlies the development of CVD risk factors in offspring born to metabolically compromised pregnancies. Female mice heterozygous for leptin receptor deficiency (Hetdb) were used as a model of maternal metabolic dysfunction. Wild type (Wt) offspring from Wt or Hetdb pregnancies were examined as either neonates or adults fed a control diet (CD) or a high fat/fructose (HFF) diet. Aim 1 of my study was to determine the effect of a metabolically compromised pregnancy on developmental adipogenesis. Measurement of whole-body fat mass and plasma resistin revealed that fat accumulation was heightened in neonates born to the Hetdb vs. Wt dams. Cell size distribution data confirmed the presence of larger-sized adipocytes in the inguinal SAT (iSAT) of neonates from the Hetdb pregnancy. Oil Red O staining, Western Blot and qPCR demonstrated a higher adipogenic potential in progenitor cells isolated from neonates born to the Hetdb pregnancy. Aim 2 of my study was to determine if SAT dysfunction is associated with CVD risk factors in offspring born to dams with metabolic dysfunction. Offspring exposed to Hetdb pregnancy had a predisposition for developing risk factors associated with CVD in adulthood. Higher circulating free fatty acids were accompanied by impairment of insulin-stimulated inhibition of lipolysis, indicating the manifestation of adipose tissue dysfunction. The differences in distribution of adipocyte diameter observed shortly after birth persisted into adulthood in CD-fed offspring, suggesting a predisposition to hypertrophic dysfunction, the cause of insulin resistance in adipocytes. In vitro differentiation studies in isolated adipocyte progenitors revealed that the intrinsic differentiation capacity of adipocyte-derived stem cells was not the mechanism responsible for impaired SAT function. In conclusion, intrauterine exposure to metabolic dysfunction leads to accelerated developmental adipogenesis and a later-life perturbation in lipid handling. Therefore, CVD risk may arise from SAT dysfunction programmed during the critical perinatal window of SAT development. Keywords: Fetal programming, adipogenesis, cardiovascular disease
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    Microscale Tissue Engineering for the Study and Treatment of Diabetes
    (2018-12-12) Yu, Yang; Ungrin, Mark D.; Huang, Carol T. L.; Rancourt, Derrick E.
    Islet transplantation is a promising approach to the treatment of insulin-dependent diabetes. However, a major clinical challenge is inefficient survival and engraftment of the transplanted material. This has been associated with insufficient oxygen and nutrition delivery after loss of the endogenous capillaries, and stress induced during islet isolation and culture. Quantitative modelling of oxygen delivery predicts significant advantages for smaller islets, and consistent with this concept, smaller human islets have also performed better than larger ones in clinical settings. In order to understand and overcome these limitations for both research and clinical applications, we have established a microscale tissue engineering approach that is capable of consistently and efficiently generating size-controlled pseudoislets from human donor islets, yielding improved survival and function both in vitro and in vivo. We then combined this platform with advanced statistical methodologies and laboratory automation systems to enable assessment of large numbers of modifying factors (and their interactions) identified from the literature in parallel. This project has yielded a substantial improvement in the consistency and efficacy of islet cell packaging for transplantation, and laid a foundation for rapid transition to the clinic.
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    Novel signaling target of prolactin receptor in pancreatic β-cells
    (2018-06-15) Makkar, Guneet; Huang, Carol T. L.; Chen, S. R. Wayne; Slater, Donna M.; Riabowol, Karl T.
    Prolactin receptor mediated β-cell mass adaptation is essential for glucose homeostasis during pregnancy. In this study, we have identified Lrrc55 as a novel downstream target of prolactin receptor in pancreatic β-cells. Lrrc55 is an auxiliary subunit of BK channels which is expressed in pancreatic islets at a very low level. During pregnancy, Lrrc55 undergoes ~70 fold increase in its expression and this increase is restricted to β-cells. Exposure of islets to diabetic milieu for 12-48 hrs led to an increase in the expression of Lrrc55, although the change was not as dramatic as that seen during pregnancy. We did not observe any change in the mRNA levels of BK channel and other paralogues of Lrrc55 during pregnancy or by induction of cellular stress. Lrrc55 also protected the islets against glucolipotoxicity-induced apoptosis by attenuating pro-apopotic components such as IRE1α, CHOP, Caspase-9 and upregulating pro-survival components like BIP, Bcl-2 of the ER stress pathway. Lrrc55’s association with BK channels led us to investigate its role in insulin secretion from β-cells. We observed minimal modulation by Lrrc55 in insulin release from β-cells. Taken together, our results put forth Lrrc55 as a novel pro-survival factor in pancreatic β-cells.
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    Role of Lrrc55 in Regulation of Pancreatic β-cell Mass and Survival
    (2021-01-22) Pretorius, Marle; Huang, Carol T. L.; Riabowol, Karl T.; Lytton, Jonathan
    During pregnancy, pancreatic β-cell mass and function are increased to accommodate for the increased maternal insulin demand. This has been tied to action of the prolactin receptor, which is present on β-cells. One gene that is differentially regulated by the prolactin receptor, and highly up regulated in islets during pregnancy, is Lrrc55. Lrrc55 is a newly described protein and an auxiliary subunit of the voltage- and calcium-activated potassium channel (BK channel). Glucolipotoxicity (GLT) is a condition commonly seen in pre-diabetic individuals that can be induced in β-cells in vitro by incubation with fatty acids and glucose. Recent work from the Huang lab found that overexpression of Lrrc55 protects β-cells from GLT-induced apoptosis. The protective effect of Lrrc55 is associated with dampening of the ER stress response and preservation of the releasable pool of calcium in the ER. Thus, I hypothesized that Lrrc55 protects β-cells from GLT-induced ER stress and apoptosis by regulating ER calcium handling. I found that Lrrc55 restored the GLT-mediated decrease in expression levels of several genes in dissociated mouse islets. These genes included the insulin regulators Pdx-1 and MafA, as well as the ER calcium regulator SERCA. Lrrc55 also attenuated the GLT-induced increase in expression of the ER calcium channel RyR. Results from activity assays indicated that Lrrc55 does not alter the activity levels of SERCA or IP3R under basal conditions. Lrrc55 also attenuated GLT-mediated increase in protein expression of pro-apoptotic molecules CHOP and IRE1α, and increased activation of the anti-apoptotic molecule Akt. Together, these results suggest a role for Lrrc55 in maintaining expression of the ER calcium regulators in the presence of GLT. Overall, this study contributes to our understanding of β-cell adaptation to stress, and the processes regulating β-cell survival.