OBJECTIVEConditional gene targeting has been extensively used for in vivo analysis of gene function in β-cell biology. The objective of this study was to examine whether mouse transgenic Cre lines, used to mediate β-cell– or pancreas-specific recombination, also drive Cre expression in the brain.RESEARCH DESIGN AND METHODSTransgenic Cre lines driven by Ins1, Ins2, and Pdx1 promoters were bred to R26R reporter strains. Cre activity was assessed by β-galactosidase or yellow fluorescent protein expression in the pancreas and the brain. Endogenous Pdx1 gene expression was monitored using Pdx1tm1Cvw lacZ knock-in mice. Cre expression in β-cells and co-localization of Cre activity with orexin-expressing and leptin-responsive neurons within the brain was assessed by immunohistochemistry.RESULTSAll transgenic Cre lines examined that used the Ins2 promoter to drive Cre expression showed widespread Cre activity in the brain, whereas Cre lines that used Pdx1 promoter fragments showed more restricted Cre activity primarily within the hypothalamus. Immunohistochemical analysis of the hypothalamus from Tg(Pdx1-cre)89.1Dam mice revealed Cre activity in neurons expressing orexin and in neurons activated by leptin. Tg(Ins1-Cre/ERT)1Lphi mice were the only line that lacked Cre activity in the brain.CONCLUSIONSCre-mediated gene manipulation using transgenic lines that express Cre under the control of the Ins2 and Pdx1 promoters are likely to alter gene expression in nutrient-sensing neurons. Therefore, data arising from the use of these transgenic Cre lines must be interpreted carefully to assess whether the resultant phenotype is solely attributable to alterations in the islet β-cells.

Metformin, an old antidiabetes drug, may inhibit prostate intraepithelial neoplasia transforming to cancer lesion via reducing c-MYC, an 'old' overexpressed oncogene. This study explores chemopreventive efficacy of metformin in prostate cancer and its link to cMYC in vitro and in vivo.

Estrogen receptor-dependent organizational events between birth [postnatal day (PND) 0] and PND 14 affect development and function of porcine uterine tissues. Observations that uterotrophic effects of relaxin (RLX) in neonatal gilts were inhibited by the antiestrogen ICI 182,780 suggested that a RLX signaling system, capable of cross-talk with the estrogen receptor, evolves during a critical period for uterine programming (PND 0-14). Objectives were to determine 1) effects of age and estrogen exposure from birth on porcine uterine RLX/insulin-like 3 receptor (LGR7/LGR8) expression and 2) whether milk serves as a natural source of RLX in neonatal pigs. Uterine LGR7/LGR8 expression, detected by RT-PCR and in situ hybridization on PND 0, 7, and 14, was predominantly stromal for LGR7, myometrial for LGR8, and increased with age and after treatment with estradiol valerate (50 microg/kg body weight x d) from birth. Stromal expression of LGR7 was also detected immunohistochemically. Milk RLX concentrations declined (P < 0.001) from 17.3 +/- 1.4 ng/ml (lactation d 0) to 1.7 +/- 0.3 ng/ml (lactation d 14). RLX, present in the serum of nursing pigs on PND 0 and 1, was undetectable before nursing and in neonates fed RLX-free milk replacer for 12 h. Thus, a developmentally regulated, estrogen-sensitive LGR7 and LGR8 receptor system is present in the porcine uterus at birth and may be activated by milk-borne RLX delivered into the circulation during the first 48 h of postnatal life. Maternal lactocrine contributions to the neonatal hormonal milieu could affect the developmental programming of uterine and other somatic tissues.

Energy homeostasis involves central nervous system integration of afferent inputs that coordinately regulate food intake and energy expenditure. Here, we report that adult homozygous TNFalpha converting enzyme (TACE)-deficient mice exhibit one of the most dramatic examples of hypermetabolism yet reported in a rodent system. Because this effect is not matched by increased food intake, mice lacking TACE exhibit a lean phenotype. In the hypothalamus of these mice, neurons in the arcuate nucleus exhibit intact responses to reduced fat mass and low circulating leptin levels, suggesting that defects in other components of the energy homeostasis system explain the phenotype of Tace(DeltaZn/DeltaZn) mice. Elevated levels of uncoupling protein-1 in brown adipose tissue from Tace(DeltaZn/DeltaZn) mice when compared with weight-matched controls suggest that deficient TACE activity is linked to increased sympathetic outflow. These findings collectively identify a novel and potentially important role for TACE in energy homeostasis.

Diabetes mellitus is an enormous menace to public health globally. This chronic disease of metabolism will adversely affect the skeleton if not controlled. Both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are associated with an increased risk of osteoporosis and fragility fractures. Bone mineral density is reduced in T1DM, whereas patients with T2DM have normal or slightly higher bone density, suggesting impaired bone quality is involved. Detrimental effects of T1DM on the skeleton are more severe than T2DM, probably because of the lack of osteo-anabolic effects of insulin and other pancreatic hormones. In both T1DM and T2DM, low bone quality could be caused by various means, including but not limited to hyperglycemia, accumulation of advanced glycosylation end products (AGEs), decreased serum levels of osteocalcin and parathyroid hormone. Risk for osteoarthritis is also elevated in diabetic population. How diabetes accelerates the deterioration of cartilage remains largely unknown. Hyperglycemia and glucose derived AGEs could contribute to the development of osteoarthritis. Moreover, it is recognized that oral antidiabetic medicines affect bone metabolism and turnover as well. Insulin is shown to have anabolic effects on bone and hyperinsulinemia may help to explain the slightly higher bone density in patients with T2DM. Thiazolidinediones can promote bone loss and osteoporotic fractures by suppressing osteoblastogenesis and enhancing osteoclastogenesis. Metformin favors bone formation by stimulating osteoblast differentiation and protecting them against diabetic conditions such as hyperglycemia. Better knowledge of how diabetic conditions and its treatments influence skeletal tissues is in great need in view of the growing and aging population of patients with diabetes mellitus.