Epac2a-null mice exhibit obesity-prone nature more susceptible to leptin resistance.

BACKGROUND: The exchange protein directly activated by cAMP (Epac), which is primarily involved in cAMP signaling, has been known to be essential for controlling body energy metabolism. Epac has two isoforms: Epac1 and Epac2. The function of Epac1 on obesity was unveiled using Epac1 knockout (KO) mice. However, the role of Epac2 in obesity remains unclear. METHODS: To evaluate the role of Epac2 in obesity, we used Epac2a KO mice, which is dominantly expressed in neurons and endocrine tissues. Physiological factors related to obesity were analyzed: body weight, fat mass, food intake, plasma leptin and adiponectin levels, energy expenditure, glucose tolerance, and insulin and leptin resistance. To determine the mechanism of Epac2a, mice received exogenous leptin and then hypothalamic leptin signaling was analyzed. RESULTS: Epac2a KO mice appeared to have normal glucose tolerance and insulin sensitivity until 12 weeks of age, but an early onset increase of plasma leptin levels and decrease of plasma adiponectin levels compared with wild-type mice. Acute leptin injection revealed impaired hypothalamic leptin signaling in KO mice. Consistently, KO mice fed a high-fat diet (HFD) were significantly obese, presenting greater food intake and lower energy expenditure. HFD-fed KO mice were also characterized by greater impairment of hypothalamic leptin signaling and by weaker leptin-induced decrease in food consumption compared with HFD-fed wild-type mice. In wild-type mice, acute exogenous leptin injection or chronic HFD feeding tended to induce hypothalamic Epac2a expression. CONCLUSIONS: Considering that HFD is an inducer of hypothalamic leptin resistance and that Epac2a functions in pancreatic beta cells during demands of greater work load, hypothalamic Epac2a may have a role in facilitating leptin signaling, at least in response to higher metabolic demands. Thus, our data indicate that Epac2a is critical for preventing obesity and thus Epac2a activators may be used to manage obesity and obesity-mediated metabolic disorders.

Adenovirus-mediated overexpression of Tcfe3 ameliorates hyperglycaemia in a mouse model of diabetes by upregulating glucokinase in the liver.

AIMS/HYPOTHESIS: Transcription factor E3 (TFE3) has been shown to increase insulin sensitivity by activating insulin-signalling pathways. However, the role of TFE3 in glucose homeostasis is not fully understood. Here, we explored the possible therapeutic potential of TFE3 for the control of hyperglycaemia using a streptozotocin-induced mouse model of diabetes. METHODS: We achieved overabundance of TFE3 in streptozotocin mice by administering an adenovirus (Ad) or adeno-associated virus serotype 2 (AAV2). We also performed an oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). To explore molecular mechanisms of blood glucose control by TFE3, transcriptional studies on the regulation of genes involved in hepatic glucose metabolism were performed using quantitative real-time PCR and chromatin immunoprecipitation assay. The binding site of TFE3 in the liver Gck gene promoter was identified using deletion and site-specific mutation studies. RESULTS: Overabundance of TFE3 resulted in reduced hyperglycaemia as shown by the OGTT and ITT in streptozotocin-treated mice. We observed that TFE3 can upregulate Gck in a state of insulin deficiency. However, glucose-6-phosphatase and cytosolic phosphoenolpyruvate carboxykinase mRNA levels were decreased by Ad-mediated overexpression of Tcfe3. Biochemical studies revealed that the anti-hyperglycaemic effect of TFE3 is due to the upregulation of Gck. In primary cultured hepatocytes, TFE3 increased expression of Gck mRNA. Conversely, small interfering RNA-mediated knockdown of TFE3 resulted in a decrease in Gck mRNA. CONCLUSIONS/INTERPRETATION: This study demonstrates that TFE3 counteracts hyperglycaemia in streptozotocin-treated mice. This effect could be due to the upregulation of Gck by binding of TFE3 to its cognitive promoter region.

Prevention of cervical cancer with vaccines.

Worldwide, cervical cancer is one of the most common cancers in women. This is especially true in developing countries, where Papanicolaou smear screening, an effective preventive measure against cervical cancer, is insufficiently implemented. With growing evidence for human papillomavirus as a central etiologic factor in cervical neoplasia, development of a vaccine against this virus has emerged as an important objective in prevention of cervical cancer. International efforts in vaccine development have culminated in advancement of various vaccine strategies and initiation of human clinical trials. Reports from animal vaccine trials and early phase I human trials indicate markedly enhanced immune response through vaccination. However, the clinical significance of these results requires confirmation from long-term human trials.

Gestational trophoblastic disease. Subsequent pregnancy outcome, including repeat molar pregnancy.

OBJECTIVE: To determine subsequent reproductive outcomes in patients treated for partial molar pregnancy, complete molar pregnancy and persistent gestational trophoblastic tumors at the New England Trophoblastic Disease Center (NETDC) between June 1, 1965, and December 31, 1996. STUDY DESIGN: Questionnaires were mailed to all patients followed at the NETDC to assess subsequent pregnancy experience. All patients and their referring physicians were also requested to inform the NETDC about later pregnancies. RESULTS: Following partial mole, complete mole and persistent gestational trophoblastic tumor, our patients had 195, 1,234 and 504 later pregnancies, respectively. These patients had a later pregnancy experience comparable to that of the general population. However, after having one molar pregnancy, the risk of molar pregnancy in a later conception was about 1%. Twenty-nine of our patients had at least two episodes of molar pregnancy; following two episodes of molar pregnancy, 6 (23.1%) of 26 later conceptions resulted in another molar gestation. CONCLUSION: Patients with partial mole, complete mole and persistent gestational trophoblastic tumor can be reassured that in general they can anticipate a normal future reproductive outcome.