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Increased human consumption of high-fructose corn syrup has been linked to the marked increase in obesity and metabolic syndrome. Previous studies on the rapid effects of a high-fructose diet in mice have largely been confined to the C57BL/6 strains. In the current study, the FVB/N strain of mice that are resistant to diet-induced weight gain were used and fed a control or high-fructose diet for 48 h or for 12 wk. Many of the previously reported changes that occurred upon high-fructose feeding for 48 h in C57BL/6 mice were recapitulated in the FVB/N mice. However, the acute increases in fructolytic and lipogenic gene expression were completely lost during the 12-wk dietary intervention protocol. Furthermore, there was no significant weight gain in FVB/N mice fed a high-fructose diet for 12 wk, despite an overall increase in caloric consumption and an increase in average epididymal adipocyte cell size. These findings may be in part explained by a commensurate increase in energy expenditure and in carbohydrate utilization in high-fructose-fed animals. Overall, these findings demonstrate that FVB/N mice are a suitable model for the study of the effects of dietary intervention on metabolic and molecular parameters. Furthermore, the rapid changes in hepatic gene expression that have been widely reported were not sustained over a longer time course. Compensatory changes in energy expenditure and utilization may be in part responsible for the differences obtained between acute and chronic high-fructose feeding protocols.

Increased de novo lipogenesis (DNL) contributes to lipid disturbances prevalent in insulin resistant (IR) subjects, including dyslipidemia and NAFLD; however, the specific carbon sources that maintain DNL during hepatic IR remain unknown. To address this question, antisense oligonucleotides (ASOs) targeting glucokinase (GCK) , ketohexokinase (KHK) , lactate dehydrogenase (LDHA) , and glutamic-pyruvic transaminase 2 (GPT2) were applied to restrict substrate influx from specific lipogenic precursors. Subsequently, the rates of DNL were assessed via the deuterated water method, and triglyceride (TG) content was measured in both insulin-sensitive regular chow (RC) fed and IR six-week high-fat diet (HFD) fed C57BL6/J mice. In RC mice, there were no significant differences in hepatic DNL as a result of treatment with any ASO. Furthermore, TG content remained unchanged by most ASOs in the RC cohort, but was increased in the liver with the LDHA ASO (Con: 7.4±0.2 μg/mg; LDHA: 16.9±1.2 μg/mg; p Conclusion: RC fed mice maintain DNL despite restricting specific carbon precursors; however, in HFD-fed mice, glucose, lactate, and alanine are all necessary substrates for maintaining aberrantly elevated rates of DNL, and any substrate restraint is associated with reduced DNL. These findings expound how specific carbon fluxes support DNL in IR and may inform the development of novel therapies for dyslipidemia. Disclosure J.W.Strober: None. L.M.Paolella: None. R.Suh: None. B.T.Hubbard: None. S.Murray: Employee; Ionis Pharmaceuticals. D.F.Vatner: None. Funding NIH T32 (DK007058) NIH R (DK124272)

Objective Adult polyglucosan body disease (APBD) is an adult‐onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease. Methods We characterized the effects of knocking out two pro‐glycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified. Results APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro‐ and micro‐gliosis in the brains of GYS1‐ and PPP1R3C‐deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies. Interpretation GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients.

Exposure to psychosocial stressors and ensuing stress physiology have been associated with spontaneous invasive mammary tumors in the Sprague-Dawley rat model of human breast cancer. Mammary gland (MG) development is a time when physiologic and environmental exposures influence breast cancer risk. However, the effect of psychosocial stress exposure on MG development remains unknown. Here, in the first comprehensive longitudinal study of MG development in nulliparous female rats (from puberty through young adulthood; 8-25 wks of age), we quantify the spatial gradient of differentiation within the MG of socially stressed (isolated) and control (grouped) rats. We then demonstrate that social isolation increased stress reactivity to everyday stressors, resulting in downregulation of glucocorticoid receptor (GR) expression in the MG epithelium. Surprisingly, given that chemical carcinogens increase MG cancer risk by preventing normal terminal end bud (TEB) differentiation, chronic isolation stress did not alter TEBs. Instead, isolation blunted MG growth and alveolobular differentiation and reduced epithelial cell proliferation in these structures. Social isolation also enhanced corpora luteal progesterone at all ages but reduced estrogenization only in early adulthood, a pattern that precludes modulated ovarian function as a sufficient mechanism for the effects of isolation on MG development. This longitudinal study of natural variation provides an integrated view of MG development and the importance of increased GR activation in nulliparous ductal growth and alveolobular differentiation. Thus, social isolation and its physiological sequelae disrupt MG growth and differentiation and suggest a contribution of stress exposure during puberty and young adulthood to the previously observed increase in invasive MG cancer observed in chronically socially-isolated adult Sprague-Dawley rats.

Exposure to unremitting psychosocial stressors common to underserved populations (i.e., social marginalization and isolation, economic uncertainty, and racism) manifest in physiologic changes that are associated with highly aggressive mammary cancer. Many environmental exposures that influence breast cancer risk in adulthood occur earlier in life during the time of mammary gland development. However, the effect of stress physiology on mammary gland development and its link to breast cancer remains unknown. In a model of psychosocial stress (social isolation), we studied whether a social isolation-induced stress response would affect mammary gland development. To this end, we used the Sprague Dawley rat, where there is an established effect of psychosocial stress on increasing later-life mammary cancer risk. Here, we found that post-weaning social isolation was associated with decreased ductal differentiation and increased mammary stem cells (MaSC). Using an in vitro model, we next determined if glucocorticoid receptor activation increased MaSC survival through direct and paracrine mechanisms. Our findings provide evidence that social stressors induce glucocorticoid exposure and decrease mammary gland differentiation leading to an increased MaSC population, potentially contributing to a greater mammary cancer risk. Citation Format: Marianna B. Johnson, Joscelyn N. Hoffmann, Hannah M. You, Ahmad B. Allaw, Jordan W. Strober, Matthew J. Brady, Martha K. McClintock, Suzanne D. Conzen. Psychosocial stress exposure results in inhibition of mammary gland development and increased mammary stem cells in a rat model of breast cancer [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B53.