Fibroblast growth factor (FGF)21 is an endocrine hormone that is expressed in multiple tissues and functions physiologically to maintain energy homeostasis. FGF21 is being pursued as a therapeutic target for diabetes and obesity because of its rapid and potent effects on improving insulin sensitivity. However, whether FGF21 enhances insulin sensitivity under physiologic conditions remains unclear. Here, we show that liver-derived FGF21 enters the circulation during fasting but also remains present and functional during the early stage of refeeding. After a prolonged fast, FGF21 acts as an insulin sensitizer to overcome the peripheral insulin resistance induced by fasting, thereby maximizing glucose uptake. Likewise, FGF21 is produced from the liver during overfeeding and mitigates peripheral insulin resistance. DIO FGF21 liver-specific knockout, but not FGF21 adipose-specific knockout, mice have increased insulin resistance and decreased brown adipose tissue–mediated glucose disposal. These data are compatible with the concept that FGF21 functions physiologically as an insulin sensitizer under conditions of acute refeeding and overfeeding.

SUMMARY FGF21 is an endocrine hormone that regulates energy homeostasis and insulin sensitivity. The mechanism of FGF21 action and the tissues responsible for these effects have been controversial, with both adipose tissues and the central nervous system being identified as the target site mediating FGF21-dependent increases in insulin sensitivity, energy expenditure, and weight loss. Here we show that while FGF21 signaling to adipose tissue is required for the acute insulin sensitizing effects of FGF21, FGF21 signaling to adipose tissue is not required for its chronic effects to increase energy expenditure and lower body weight. Also, in contrast to previous studies, we found that adiponectin is dispensable for the metabolic effects of FGF21 in increasing insulin sensitivity and energy expenditure. Instead, FGF21 acutely enhances insulin sensitivity through actions on brown adipose tissue. Our data reveal that the acute and chronic effects of FGF21 can be dissociated through adipose-dependent and -independent mechanisms.

Pseudomonas aeruginosa is an important pathogen commonly implicated in nosocomial infections. The occurrence of multidrug-resistant (MDR) P. aeruginosa strains is increasing worldwide and limiting our therapeutic options. The MDR phenotype can be mediated by a variety of resistance mechanisms, and the corresponding relative biofitness is not well established. We examined the prevalence, resistance mechanisms, and susceptibility of MDR P. aeruginosa isolates (resistant to >3 classes of antipseudomonal agents [penicillins/cephalosporins, carbapenems, quinolones, and aminoglycosides]) obtained from a large, university-affiliated hospital. Among 235 nonrepeat bloodstream isolates screened between 2005 and 2007, 33 isolates (from 20 unique patients) were found to be MDR (crude prevalence rate, 14%). All isolates were resistant to carbapenems and quinolones, 91% were resistant to penicillins/cephalosporins, and 21% were resistant to the aminoglycosides. By using the first available isolate for each bacteremia episode (n ‫؍‬ 18), 13 distinct clones were revealed by repetitive-element-based PCR. Western blotting revealed eight isolates (44%) to have MexB overexpression. Production of a carbapenemase (VIM-2) was found in one isolate, and mutations in gyrA (T83I) and parC (S87L) were commonly found. Growth rates of most MDR isolates were similar to that of the wild type, and two isolates (11%) were found to be hypermutable. All available isolates were susceptible to polymyxin B, and only one isolate was nonsusceptible to colistin (MIC, 3 mg/liter), but all isolates were nonsusceptible to doripenem (MIC, >2 mg/liter). Understanding and continuous monitoring of the prevalence and resistance mechanisms of MDR P. aeruginosa would enable us to formulate rational treatment strategies to combat nosocomial infections.Pseudomonas aeruginosa is an important pathogen commonly implicated in serious nosocomial infections such as pneumonia and sepsis. The occurrence of multidrug-resistant P. aeruginosa strains is increasing worldwide and limiting our therapeutic options. Resistance in P. aeruginosa may be mediated via several distinct mechanisms (3, 13). In multidrug-resistant isolates, the relative contributions of different molecular mechanisms toward phenotypic multidrug resistance are not well established. While there are multiple surveillance studies tracking the resistance of P. aeruginosa to various antimicrobial agents over the years (6, 7), studies reporting trends in concomitant resistance to multiple agents over time are scarce.A hypermutable state is often observed in multidrug-resistant pathogens causing chronic infections in cystic fibrosis patients. It is often related to defects in genes involved in the mismatch repair system (e.g., mutS and mutL). It is also commonly believed that in multidrug-resistant P. aeruginosa isolates, reduced virulence may result due to decreased biofitness. However, recent data suggest otherwise, and multidrug-resistant P. aeruginosa may remain fully pathogenic (8).Many first-line agents are ...