Differential effects of acute versus chronic dietary fructose consumption on metabolic responses in FVB/N mice.

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.

GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease.

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.

Dietary Fructose Consumption and Triple-Negative Breast Cancer Incidence.

In the past century the western world has found a way to combat most communicative diseases; however, throughout that time the prevalence of obesity, hyperglycemia, and hyperlipidemia have drastically increased. These symptoms characterize metabolic syndrome-a non-communicable disease which has become one of the greatest health hazards of the world. During this same time period the western diet had dramatically changed. Homecooked meals have been replaced by highly-processed, calorically dense foods. This conversion to the current western diet was highlighted by the incorporation of high-fructose corn syrup (HFCS) into sweetened beverages and foods. The consumption of large amounts of dietary sugar, and fructose in particular, has been associated with an altered metabolic state, both systemically and in specific tissues. This altered metabolic state has many profound effects and is associated with many diseases, including diabetes, cardiovascular disease, and even cancer (1). Specific types of cancer, like triple-negative breast cancer (TNBC), are both responsive to dietary factors and exceptionally difficult to treat, illustrating the possibility for preventative care through dietary intervention in at risk populations. To treat these non-communicable diseases, including obesity, diabetes, and cancer, it is imperative to understand systemic and localized metabolic abnormalities that drive its progression. This review will specifically explore the links between increased dietary fructose consumption, development of metabolic disturbances and increased incidence of TNBC.

Psychosocial Stress Exposure Disrupts Mammary Gland Development.

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.