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Context: Given the promising effects of prolonged treatment with beta2-agonist on insulin sensitivity in animals and non-diabetic individuals, the beta2-adrenergic receptor has been proposed as a target to counter peripheral insulin resistance. On the other hand, rodent studies also reveal that beta2-agonists acutely impair insulin action, posing a potential caveat for their use in treating insulin resistance., Objective: To assess the impact of beta2-agonist on muscle insulin action and glucose metabolism and identify the underlying mechanism(s) in 10 insulin-resistant subjects., Methods and Participants: In a cross-over design, we assessed the effect of beta2-agonist on insulin-stimulated muscle glucose uptake during a 3-h hyperinsulinemic isoglycemic clamp with and without intralipid infusion in 10 insulin-resistant overweight subjects. Two hours into the clamp, we infused beta2-agonist. We collected muscle biopsies before, two hours into and by the end of the clamp and analyzed them using metabolomic and lipidomic techniques., Results: We establish that beta2-agonist, independently from and additively to intralipid, impairs insulin-stimulated muscle glucose uptake via different mechanisms. In combination, beta2-agonist and intralipid nearly eliminates insulin-dependent muscle glucose uptake. While both beta2-agonist and intralipid elevated muscle glucose-6-phosphate, only intralipid caused accumulation of downstream muscle glycolytic intermediates, whereas beta2-agonist attenuated incorporation of glucose into glycogen., Conclusions: Our findings suggest that beta2-agonist inhibits glycogenesis while intralipid inhibits glycolysis in skeletal muscle of insulin-resistant individuals. These results should be addressed in future treatment of insulin resistance with beta2-agonist., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Study Objectives: Insufficient sleep may attenuate weight loss, but the role of sleep in weight loss maintenance is unknown. Since weight regain after weight loss remains a major obstacle in obesity treatment, we investigated whether insufficient sleep predicts weight regain during weight loss maintenance., Methods: In a randomized, controlled, two-by-two factorial study, 195 adults with obesity completed an 8-week low-calorie diet and were randomly assigned to 1-year weight loss maintenance with or without exercise and liraglutide 3.0 mg/day or placebo. Sleep duration and quality were measured before and after the low-calorie diet and during weight maintenance using wrist-worn accelerometers (GENEActiv) and Pittsburgh Sleep Quality Index (PSQI). To test associations between insufficient sleep and weight regain, participants were stratified at randomization into subgroups according to sleep duration (5)., Results: After a diet-induced 13.1 kg weight loss, participants with short sleep duration at randomization regained 5.3 kg body weight (p = .0008) and had less reduction in body fat percentage compared with participants with normal sleep duration (p = .007) during the 1-year weight maintenance phase. Participants with poor sleep quality before the weight loss regained 3.5 kg body weight compared with good quality sleepers (p = .010). During the weight maintenance phase, participants undergoing liraglutide treatment displayed increased sleep duration compared with placebo after 26 weeks (5 vs. -15 min/night) but not after 1 year. Participants undergoing exercise treatment preserved the sleep quality improvements attained from the initial weight loss., Conclusions: Short sleep duration or poor sleep quality was associated with weight regain after weight loss in adults with obesity., (© Sleep Research Society 2022. Published by Oxford University Press on behalf of the Sleep Research Society.)

Objectives: Despite the increasing incidence of carbapenem-intermediate or -resistant Enterobacteriaceae (CIRE), risk factors associated with CIRE infections have not been well defined. This study characterizes factors associated with CIRE among two different source populations., Methods: A case-control study was performed at a tertiary care medical centre between January 2005 and December 2009. Cases were adults with a culture-confirmed Enterobacteriaceae infection with reduced susceptibility to meropenem or ertapenem. The CIRE cases were matched 1:1 to patients from two different control series: (i) those with carbapenem-susceptible Enterobacteriaceae (CSE) infections; and (ii) inpatients residing on the same ward within 30 days of CIRE culture date. Logistic regression was used to identify variables independently associated with CIRE among each source population. Restricted multivariate analyses were performed to determine if covariates predictive of CIRE varied by infecting organism or presence of the bla(KPC) gene., Results: There were 102 cases of CIRE during the study period. The only covariate independently associated with CIRE in all multivariate analyses was the cumulative number of prior antibiotic exposures. Compared with CSE controls, the odds ratios (95% confidence interval) were 1.43 (1.19-1.72), 2.05 (1.70-2.47) and 2.93 (2.43-3.53) for 1, 2 and ≥ 3 antibiotic exposures, respectively. The strength of this association was comparable for the hospitalized control group and analyses stratified by organism and presence of the bla(KPC) gene., Conclusions: A patient's cumulative antibiotic exposure history is likely to be more important than any one specific exposure when determining the likelihood of developing a CIRE infection.

To investigate the control of zygotic genome expression in two-cell mouse embryos, we studied transcription factors required for transient expression of microinjected DNA constructs driven by the promoter of one of the earliest genes activated after fertilization in this system, the heat shock gene hsp70. Cis-acting elements required for hsp70 activation were first investigated by mutational analysis. Mutation of the TATA box and a proximal GC box strongly inhibited construct expression, while that of a CCAAT box had no effect. Transcription factors binding the wild-type hsp70 promoter were then titrated in vivo by coinjecting the construct with double-stranded oligodeoxyribonucleotides containing definite consensus sequences. Wild-type GC box oligonucleotides strongly inhibited construct expression, while those containing mutated GC boxes, wild-type CCAAT boxes, and heat shock elements had no effects. Finally, construct expression was challenged by coinjecting antibodies to specific transcription factors. Antibodies to factor Sp1 depressed construct expression in a dose-dependent manner, while those to Sp2, HSF1 and HSF2 were ineffective. These results pinpoint the Sp1 transcription factor as an absolute requirement for activation of the hsp70 gene promoter in two-cell mouse embryos, and make this factor a candidate for a major regulator of the onset of murine zygotic genome expression.

A central step in the transcriptional activation of heat shock genes is the binding of the heat shock factor (HSF) to upstream heat shock elements (HSEs). In vertebrates, HSF1 mediates the ubiquitous response to stress stimuli, while the role of a second HSE-binding factor, HSF2, is still unclear. In this work we show that both factors are expressed in a wide range of murine tissues and each exists as two splicing isoforms. Although HSFs are virtually ubiquitous proteins, their abundance is predominant in testis and variable among other tissues, indicating specific regulations of their expression. A low level of DNA-binding activity of HSF1, detected in many tissues, is probably physiological and is not explained by an anomalous regulation of one of the two isoforms. Our observations suggest that these regulatory proteins may all have roles in fully developed tissues. This possibility is not mutually exclusive of a role of HSF2 during cellular differentiation and tissue development [L. Sistonen, K. D. Sarge and R. I. Morimoto (1994), Mol. Cell. Biol., 14, 2087-2099].

The effect of hyperthermia on mammalian oocyte maturation was studied by allowing preovulatory mouse oocytes to mature spontaneously for 17 h in vitro under controlled temperature conditions. At the end of culture, oocytes were screened for their maturation stage and for chromosome morphology and number. Mild hyperthermic conditions (38.5-40.0 degrees C) during maturation specifically disturbed the process of bivalent chromosome disjunction, but not other maturation steps, by blocking oocytes at the metaphase I stage and preventing cells from entering subsequent maturation steps. Some oocytes that had reached metaphase II under hyperthermic conditions had chromosome imbalance. Oocytes matured at 40.0 degrees C displayed chromosome morphological abnormalities, including altered sister chromatid separation and nucleus/nuclei formation, at a frequency significantly higher than oocytes matured at 37.0-39.0 degrees C. When incubation temperature was raised above 40.0 degrees C, increasing fractions of oocytes were inhibited from entering initial maturation steps. We conclude that hyperthermia during mammalian oocyte maturation specifically damages the process of bivalent chromosome disjunction and induces the appearance of chromosome structural defects and imbalance in unfertilized eggs.