Dairy farmer, engagement and understanding of One Health and antimicrobial resistance - a pilot survey from the lower north island of Aotearoa New Zealand.

BACKGROUND: Reducing antimicrobial resistance (AMR) requires a multidisciplinary One Health approach, which necessitates buy-in from all stakeholders. In Aotearoa New Zealand, where the dairy industry is one of the largest users of antimicrobials, there are ongoing efforts to optimise antimicrobial usage (AMU) to minimise the development of AMR. These include regulations around the veterinary authorisation of the use of antibiotics by farmers without the need for a specific prescription ("the RVM process") and programmes such as the New Zealand Veterinary Association's antibiotic 'Traffic Light System'. The goal of this pilot survey was to develop and trial a questionnaire to determine how much Aotearoa dairy farmers understand about One Health, AMR, the RVM process and how their actions regarding AMU affect the wider environment. METHODS: A 55-question semi-structured questionnaire was piloted on 15 dairy farms in the Lower North Island of Aotearoa New Zealand via an in-person semi-structured interview between September and November 2021. RESULTS: None of the interviewed farmers could define the term One Health. However, the majority found the RVM process to be of use on their farm, although admitted they generally felt frustration regarding AMR, seeing it as a blockage to productivity, and lacked awareness regarding how their actions were related to its development. Of the farmers interviewed over half had not heard of the traffic light system, and of those who had, one admitted they refused to adhere to it. CONCLUSIONS: This survey's novel findings have highlighted that there are notable gaps within dairy farmer understanding of AMU, AMR and One Health as well as highlighting that veterinarians could do more to keep their clients informed of their important role within One Health. There is still a lot more work to do with regards to vets, farmers and industry representatives working together to embrace One Health. Simple solutions would be to encourage farmers returning unused drugs to their veterinarians for correct disposal and to actively engage farmers further regarding AMU and AMR, so that these end-product users do not feel disconnected from the process.

Pain Assessment in Cattle by Use of Numerical Rating and Visual Analogue Scales-A Systematic Review and Meta-Analysis.

Subjective pain assessment in cattle is contingent upon the observer's experience and attitude. Studies of pain assessment in cattle by veterinarians and farmers using different pain scales have been published. This systematic review and meta-analysis aimed to describe and compare the pain scores given by veterinarians and producers for different procedures and conditions using either a NRS or VAS. The literature search was conducted with PubMed (MEDLINE) and Agricola, using defined search terms (e.g., peer-reviewed). A total of 842 articles were identified. After screening of duplicates, abstracts, and full texts, a total of 16 articles were included in this systematic review. Different pain scales were used for the included studies (NRS 0-10 for eight studies, NRS 1-10 for six studies, NRS 1-10 and VAS 0-10 for one study, and VAS 0-1 for one study). Most studies (n = 11) originated from the European Union. Mean values for pain scores differed significantly between studies included in the meta-analysis for both NRS 0-10 and 1-10. The findings of this study indicated that comparison of pain scoring used in different studies is difficult due to use of different pain scales and varying nomenclature, and that many variables (such as age and gender) influence pain scoring.

Assessing Alternatives to Locomotion Scoring for Detecting Lameness in Dairy Cattle in Tanzania: Infrared Thermography.

Lameness detection is a significant challenge. Locomotion scoring (LS), the most widely used system for detecting lameness, has several limitations, including its subjective nature and the existence of multiple systems, each with its own advantages and disadvantages. Therefore, this study aimed to evaluate whether the foot skin temperature (FST) of hind limbs, as measured using infrared thermography (IRT), could potentially be used as an alternative on Tanzanian dairy farms. Each of the three study farms were visited twice during the afternoon milking on consecutive days, with a total of 170 cows assessed. DairyNZ LS (4-point scale (0-3)) was undertaken on the first day as the cows exited the milking parlour after being milked, while on the following day, the plantar aspect of the hind limbs of the cows was thermally imaged while they were standing in the milking parlour, using a handheld T650sc forward-looking infrared camera. Mean FST was higher for cows with a locomotion score of 1 than those with a score of 0; higher for cows with a locomotion score of 2 than those with a score of 1; and higher for cows with a locomotion score of 3 than those with a score of 2, with each one-unit locomotion score increase being associated with a 0.57 °C increase in mean temperature across all zones. The optimal cut-off point of 38.0 °C for mean temperature across all zones was identified using a receiver operator characteristic curve. This cut-off point had a sensitivity of 73.2% and a specificity of 86.0% for distinguishing cows with a locomotion score ≥ 2 (clinical lameness). The prevalence of clinical lameness across all three farms was 33%, which meant that only 72% of cows with a mean FST across all zones ≥ 38.0 °C had been identified as clinically lame using LS. This study confirmed that IRT has the potential to be used to detect lameness on Tanzanian dairy farms. However, before it can be widely used, improvements in accuracy, especially specificity, are needed, as are reductions in equipment (IR camera) costs.

Evaluating the Effect of Preventative Trimming on Distance from the Sole Surface to the Distal Phalanx Using Ultrasonography for Lameness Prevention in Pasture-Based Dairy Cows.

One common management strategy used to reduce the risk of lameness is prophylactic claw trimming. However, in pasture-based cattle, there is a concern that the immediate reduction in sole thickness resulting from sole trimming will lead to medium-to-long-term reductions in sole thickness, which may increase the risk of lameness. Nevertheless, there is a lack of data on sole thickness and trimming in pasture-based cows. Therefore, the aim of this study was to evaluate the effect of trimming on sole thickness over the medium-to-long term, as estimated using the ultrasound-measured distance from the external claw sole surface to the distal phalanx (DDP) and of DDP on the interval between calving and increased locomotion scores. A total of 38 cows were randomly selected from a 940-cow spring calving dairy farm in the North Island of New Zealand; 18 were allocated to the ultrasound hoof-trimming group and 20 were allocated to the ultrasound non-trimming group. Starting in May 2018, at the end of the 2017/18 lactation, ultrasound measurements of DDP of the right hind hoof were made on all 38 cows, and the hindlimbs of the trimming group cows were trimmed by an experienced professional hoof trimmer using the five-step Dutch method. This was repeated in October 2018 (early lactation) and May 2019 (late lactation). After calving, the cows were locomotion scored fortnightly until the end of lactation using the 4-point (0-3) scale DairyNZ system. The effect of DDP on the interval between calving and the first locomotion scores ≥1 and ≥2 was assessed using Cox proportional hazards models, and the association between trimming and DDP was explored using linear mixed models. The results suggest that DDP has no effect on the time to locomotion scores ≥1 or ≥2, although the wide confidence intervals of the latter suggest that more data are needed before any definitive conclusions can be drawn. The study failed to find any clinically important impact of prophylactic trimming on DDP. This is likely related to the finding that cows with the highest DDP at the first trimming were identified by the hoof trimmer as those needing the most trimming. The results of this study thus suggest that if the Dutch five-step method is properly applied, it is unlikely to affect sole thickness over the short-to-medium term in pasture-based cattle.

The effect of self-reported balance confidence on community integration after brain injury: an observational study.

OBJECTIVE: To evaluate the correlation between self-reported balance confidence and community integration related to home management for community-dwelling adults with acquired brain injury (ABI). METHODS: This is a study of 141 participants over the age of 18 with a history of ABI, living in the community, who completed an online survey. The survey included a series of demographic questions followed by the Activities-Specific Balance Confidence Scale (ABC) and the Home Integration subscale of the Community Integration Questionnaire (CIQ-H). RESULTS: Data from 119 completed surveys were included in the analysis. Significant positive correlations were found between the ABC and the CIQ-H total scores (rs = 0.241, p = 0.008). There was no significant difference between CIQ-H total scores in individuals by injury type (traumatic vs non-traumatic) or by level of severity (mild, moderate, severe) (p > 0.05). There was no significant difference between ABC total scores by injury type (p > 0.05). CONCLUSIONS: Higher levels of balance confidence may be associated with improved community integration related to home management for individuals with traumatic and non-traumatic BI. This study's results support future research to evaluate the integration of strategies to improve balance confidence as a component of interdisciplinary assessment and rehabilitation to maximize community integration in community-dwelling adults with ABI.

Evaluating Alternatives to Locomotion Scoring for Detecting Lameness in Pasture-Based Dairy Cattle in New Zealand: In-Parlour Scoring.

Earlier detection followed by efficient treatment can reduce the impact of lameness. Currently, locomotion scoring (LS) is the most widely used method of early detection but has significant limitations in pasture-based cattle and is not commonly used routinely in New Zealand. Scoring in the milking parlour may be more achievable, so this study compared an in-parlour scoring (IPS) technique with LS in pasture-based dairy cows. For nine months on two dairy farms, whole herd LS (4-point 0−3 scale) was followed 24 h later by IPS, with cows being milked. Observed for shifting weight, abnormal weight distribution, swollen heel or hock joint, and overgrown hoof. Every third cow was scored. Sensitivity and specificity of individual IPS indicators and one or more, two or more or three positive indicators for detecting cows with locomotion scores ≥ 2 were calculated. Using a threshold of two or more positive indicators were optimal (sensitivity > 92% and specificity > 98%). Utilising the IPS indicators, a decision tree machine learning procedure classified cows with locomotion score class ≥2 with a true positive rate of 75% and a false positive rate of 0.2%. IPS has the potential to be an alternative to LS on pasture-based dairy farms.

Evaluating Alternatives to Locomotion Scoring for Lameness Detection in Pasture-Based Dairy Cows in New Zealand: Infra-Red Thermography.

Lameness in cattle is a complex condition with huge impacts on welfare, and its detection is challenging for the dairy industry. The present study aimed to evaluate the association between foot skin temperature (FST) measured using infrared thermography (IRT) and locomotion scoring (LS) in dairy cattle kept at pasture. Data were collected from a 940-cow dairy farm in New Zealand. Cows were observed at two consecutive afternoon milkings where LS was undertaken at the first milking (4-point scale (0-3), DairyNZ). The next day, cows were thermally imaged from the plantar aspect of the hind feet using a handheld T650sc forward-looking infrared camera (IRT). The association between FST and locomotion score was analysed using a generalised linear model with an identity link function and robust estimators. ROC curves were performed to determine optimal threshold temperature cut-off values by maximising sensitivity and specificity for detecting locomotion score ≥ 2. There was a linear association between individual locomotion scores and FST. For mean temperature (MT), each one-unit locomotion score increase was associated with a 0.944 °C rise in MT. Using MT at a cut-off point of 34.5 °C produced a sensitivity of 80.0% and a specificity of 92.4% for identifying cows with a locomotion score ≥ 2 (lame). Thus, IRT has a substantial potential to be used on-farm for lameness detection. However, automation of the process will likely be necessary for IRT to be used without interfering with farm operations.

ECOG and BMI as preoperative risk factors for severe postoperative complications in ovarian cancer patients: results of a prospective study (RISC-GYN-trial).

BACKGROUND: Accompanying co-morbidities in patients with ovarian cancer are of major relevance for scheduling debulking surgery, especially in the anesthesiological consultations. Aim of this study was to evaluate the impact of co-morbidities and patient characteristics on postoperative complications. METHODS: Patients undergoing maximal cytoreductive surgery were prospectively enrolled from October 2015 to January 2017. Various variables were recorded, such as the Charlson comorbidity index, Eastern cooperative oncology group scale of performance status (ECOG PS) and the American society of anesthesiologists physical status classification system (ASA PS). Surgical complications were graded using the Clavien-Dindo criteria. Logistic regression models were used to analyze risk factors for severe postoperative complications. RESULTS: Of 106 enrolled patients, 19 (17.9%) developed severe postoperative complications grade ≥ IIIb according to Clavien-Dindo criteria. In the multivariable regression analysis impaired (ECOG PS) > 1 (odds ratio OR) 13.34, 95% confidence interval (CI) 1.74-102.30, p = 0.01), body mass index (BMI) > 25 kg/m2 (OR 10.48, 95% CI 2.38-46.02, p = 0.002) along with the use of intraoperative norepinephrine > 0.11 µg/kg/min (OR 4.69, 95% CI 1.13-19.46, p = 0.03) and intraoperative fresh frozen plasma (FFP) > 17 units (OR 4.11, 95% CI 1.12-15.14, p = 0.03) appeared as significant predictors of severe postoperative complications. CONCLUSION: We demonstrated that neither the presence of a certain comorbidity nor the summation of the co-morbidities were associated with adverse outcome. Patient characteristics, such as ECOG PS > 1 and obesity (BMI > 25 kg/m2), are highly predictive factors for severe postoperative complications. The analysis of intraoperative data showed that the need for more than > 0.11 µg/kg/min of norepinephrine and transfusions of FFPs more than 17 units were strongly associated with severe postoperative complications.

Effects of sarcopenia and malnutrition on morbidity and mortality in gynecologic cancer surgery: results of a prospective study.

BACKGROUND: Malnutrition and sarcopenia often occur simultaneously in cancer patients and are thought to have harmful effects on both surgical and oncological outcomes. Therefore, we want to evaluate the effects of sarcopenia and malnutrition on severe postoperative complications and overall survival in gynecologic cancer patients. METHODS: We assessed nutritional parameters and run a bioelectrical impedance analysis in 226 women. Extracellular mass to body cell mass index, phase angle alpha, muscle mass, and fat mass were evaluated. To determine if patients suffer from sarcopenia, we ran the Timed 'Up and Go' test, performed hand grip strength, and calculated a skeletal muscle index. Postoperative complications were categorized using Clavien-Dindo Classification. Utilizing ROC analysis and logistic regression, we determined predictive clinical factors for severe postoperative complications. Kaplan-Meier method and log-rank test were used for overall survival analysis. RESULTS: Of the 226 female patients, 120 (53%) had a BMI ≥ 25 kg/m2 , 56 (26%) had a phase angle < 4.75°, and 68 (32%) were sarcopenic according to skeletal muscle index < 27%. Within 30 days after surgery, 40 (18%) patients developed severe postoperative complications, and 4% had died. According to multivariable regression analysis, ECOG status > 1 (OR 4.56, 95% CI: 1.46-14.28, P = 0.009), BMI ≥ 25 kg/m2 (OR 8.22, 95% CI: 3.01-22.48, P < 0.001), phase angle < 4.75° (OR 3.95, 95% CI: 1.71-9.10, P = 0.001), and tumour stage ≥ III A (OR 3.65, 95% CI: 1.36-9.76, P = 0.01) were predictors of severe postoperative complications. During 59 months of follow-up, 108 (48%) patients had died. According to multivariable Cox regression ECOG status > 1 (HR 2.51, 95% CI: 1.25-5.03, P = 0.01), hypoalbuminemia (HR 2.15, 95% CI: 1.28-3.59, P = 0.004), phase angle < 4.5° (HR 1.76, 95% CI 1.07-2.90, P = 0.03), tumour stage ≥ III A (HR 2.61, 95% CI: 1.53-4.45, P < 0.001), and severe postoperative complications (HR 2.82, 95% CI: 1.80-4.41, P < 0.001) were predictors of overall mortality. CONCLUSIONS: We observed that preoperatively assessed ECOG status > 1, BMI > 25 kg, as well as phase angle alpha < 4.75° and FIGO stage ≥ III A are significantly associated with severe postoperative complications within the first month. Whereas ECOG status > 1, hypoalbuminemia, phase angle < 4.5° as well as FIGO stage ≥ III A and severe postoperative complications within 30 days correlate significantly with poor overall survival.

TYK2 licenses non-canonical inflammasome activation during endotoxemia.

The non-canonical inflammasome is an emerging crucial player in the development of inflammatory and neurodegenerative diseases. It is activated by direct sensing of cytosolic lipopolysaccharide (LPS) by caspase-11 (CASP11), which then induces pyroptosis, an inflammatory form of regulated cell death. Here, we report that tyrosine kinase 2 (TYK2), a cytokine receptor-associated kinase, is a critical upstream regulator of CASP11. Absence of TYK2 or its kinase activity impairs the transcriptional induction of CASP11 in vitro and in vivo and protects mice from LPS-induced lethality. Lack of TYK2 or its enzymatic activity inhibits macrophage pyroptosis and impairs release of mature IL-1ß and IL-18 specifically in response to intracellular LPS. Deletion of TYK2 in myeloid cells reduces LPS-induced IL-1ß and IL-18 production in vivo, highlighting the importance of these cells in the inflammatory response to LPS. In support of our data generated with genetically engineered mice, pharmacological inhibition of TYK2 reduced LPS-induced upregulation of CASP11 in bone marrow-derived macrophages (BMDMs) and of its homolog CASP5 in human macrophages. Our study provides insights into the regulation of CASP11 in vivo and uncovered a novel link between TYK2 activity and CASP11-dependent inflammation.

Role of predictive markers for severe postoperative complications in gynecological cancer surgery: a prospective study (RISC-Gyn Trial).

BACKGROUND: Surgery for gynecological cancer involves highly invasive and complex procedures potentially associated with various complications, which can cause extended hospital stays and delay of subsequent therapy, with a detrimental effect on the prognosis. The aim of this study was to explore and define the predictors of severe postoperative complications in patients undergoing surgery for gynecologic cancer. METHODS: Patients undergoing surgery for gynecologic cancers were analyzed prospectively from October 2015 through January 2017. Using validated assessment tools preoperatively, we assessed comorbidities, performance status, quality of life, nutritional and body composition by bioelectrical impedance analysis, and the surgical data of each patient. Surgical complications were graded using the Clavien-Dindo criteria. Using stepwise logistic regression models, we identified predictive markers for postoperative complications. RESULTS: Of the 226 enrolled patients, 40 (17.7%) experienced a grade ≥IIIb complication according to the Clavien-Dindo criteria. In the regression analysis, overweight/obesity (body mass index >25) (OR 6.41, 95% CI 2.38 to 17.24; p<0.001) and impaired physical functioning defined by a quality of life questionnaire (OR 4.19, 95% CI 1.84 to 9.50; p=0.001) emerged as significant predictors of postoperative complications. Moreover, postoperative complications were predicted by phase angle of bioelectrical impedance analysis <4.75° (OR 3.11, 95% CI 1.35 to 7.16; p=0.008) and Eastern Cooperative Oncology Group (ECOG) performance status >1 (OR 2.51, 95% CI 1.06 to 5.92; p=0.04). Intraoperative factors associated with higher risk of postoperative complications were increased use of norepinephrine (>11 µg/kg/min) (OR 5.59, 95% CI 2.16 to 14.44; p<0.001) and performance of large bowel resection (OR 4.28, 95% CI 1.67 to 10.97; p=0.002). CONCLUSION: In patients undergoing surgery for gynecological cancer, preoperative evaluation of performance status according to ECOG, domains of quality of life and nutritional status, as well as intraoperative monitoring of risk factors, might help to identify patients at high risk for severe postoperative complications, and thus reduce surgical morbidity and mortality.

STAT5 is required for lipid breakdown and beta-adrenergic responsiveness of brown adipose tissue.

OBJECTIVE: Increasing energy expenditure through activation of brown adipose tissue (BAT) thermogenesis is an attractive approach to counteract obesity. It is therefore essential to understand the molecular mechanisms that control BAT functions. Until now several members of the Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway have been implicated as being relevant for BAT physiology. However, whether the STAT family member STAT5 is important for the thermogenic property of adipose tissues is unknown. Therefore, we have investigated the role of STAT5 in thermogenic fat in this paper. METHODS: We performed metabolic and molecular analyses using mice that harbor an adipocyte-specific deletion of Stat5a/b alleles. RESULTS: We found that STAT5 is necessary for acute cold-induced temperature maintenance and the induction of lipid mobilization in BAT following ß3-adrenergic stimulation. Moreover, mitochondrial respiration of primary differentiated brown adipocytes lacking STAT5 was diminished. Increased sensitivity to cold stress upon STAT5 deficiency was associated with reduced expression of thermogenic markers including uncoupling protein 1 (UCP1), while decreased stimulated lipolysis was linked to decreased protein kinase A (PKA) activity. Additionally, brown remodeling of white adipose tissue was diminished following chronic ß3-adrenergic stimulation, which was accompanied by a decrease in mitochondrial performance. CONCLUSION: We conclude that STAT5 is essential for the functionality and the ß-adrenergic responsiveness of thermogenic adipose tissue.

Effects of dietary supplementation of bentonite and Saccharomyces cerevisiae cell wall on acute-phase protein and liver function in high-producing dairy cows during transition period.

The aim of this study was to investigate the efficacy of dietary endotoxin binders [bentonite (BEN) and Saccharomyces cerevisiae cell wall (SCW)] on acute-phase protein (APP) response and liver function in cows during the transition period. Twenty-four multiparous Holstein cows were randomly assigned to one of four treatment groups. The experimental groups consisted of (1) the basal diet (BD) + SCW, (2) BD + SCW + BEN, (3) BD + BEN, and (4) BD (control). Blood samples were taken at 1, 3 and 4 weeks before and 1 and 3 weeks after parturition and serum concentrations of non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), glucose, haptoglobin (Hp), serum amyloid A(SAA), albumin, g-glutamyl transferase (GGT), aspartate aminotransferase (AST), cholesterol, iron, and lipopolysaccharide (LPS) were measured. The concentrations of LPS, SAA, albumin, and Hp in the blood were within reference range at all times. The level of blood LPS was not high enough to initiate an APP response. Mean BHBA concentration was highest at 1 week after calving. For NEFA, the pattern was similar, with a peak at 1 week after calving. Cholesterol concentration was lower in the SCW group, probably due to a lower lipoprotein concentration. Mean AST concentration was highest at 1 week after calving, especially in the SCW + BEN group. The results of a current study showed that, if the carbohydrate level is not high in the diet to cause rumen acidosis, it is not profitable to supplement BEN and SCW for adsorbing endotoxins in the diet, in transition cows.

Hepatic growth hormone - JAK2 - STAT5 signalling: Metabolic function, non-alcoholic fatty liver disease and hepatocellular carcinoma progression.

The rising prevalence of obesity came along with an increase in associated metabolic disorders in Western countries. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of the metabolic syndrome and is linked to primary stages of liver cancer development. Growth hormone (GH) regulates various vital processes such as energy supply and cellular regeneration. In addition, GH regulates various aspects of liver physiology through activating the Janus kinase (JAK) 2- signal transducer and activator of transcription (STAT) 5 pathway. Consequently, disrupted GH - JAK2 - STAT5 signaling in the liver alters hepatic lipid metabolism and is associated with NAFLD development in humans and mouse models. Interestingly, while STAT5 as well as JAK2 deficiency correlates with hepatic lipid accumulation, recent studies suggest that these proteins have unique ambivalent functions in chronic liver disease progression and tumorigenesis. In this review, we focus on the consequences of altered GH - JAK2 - STAT5 signaling for hepatic lipid metabolism and liver cancer development with an emphasis on lessons learned from genetic knockout models.

STAT5 deficiency in hepatocytes reduces diethylnitrosamine-induced liver tumorigenesis in mice.

Chronic liver diseases and the development of hepatocellular carcinoma are closely linked and pose a major medical challenge as treatment options are limited. Animal studies have shown that genetic deletion of the signal transducer and activator of transcription (STAT) 5 in liver is associated with higher susceptibility to fatty liver disease, fibrosis and cancer, indicating a protective role of hepatic STAT5 in mouse models of chronic liver disease. To investigate the role of STAT5 in the etiology of liver cancer in more detail, we applied the chemical carcinogen diethylnitrosamine (DEN) to mice harboring a hepatocyte-specific deletion of Stat5 (S5KO). At 8 months after DEN injections, tumor formation in S5KO was significantly reduced. This was associated with diminished tumor frequency and less aggressive liver cancer progression. Apoptosis and inflammation markers were not changed in S5KO livers suggesting that the reduced tumor burden was not due to impaired inflammatory response. Despite reduced mRNA expression of the DEN bio-activator cytochrome P450 2e1 (Cyp2e1) in S5KO livers, protein levels were similar. Yet, delayed tumor formation in S5KO mice coincided with decreased activation of c-Jun N-terminal Kinase (JNK). Taken together, while STAT5 has a protective role in fatty liver-associated liver cancer, it exerts oncogenic functions in DEN-induced liver cancer.

Adipocyte Glucocorticoid Receptor Deficiency Attenuates Aging- and HFD-Induced Obesity and Impairs the Feeding-Fasting Transition.

Glucocorticoids (GCs) are important regulators of systemic energy metabolism, and aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiological energy metabolism depend on the GC receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR deficiency in mice significantly impacts systemic metabolism in different energetic states. Plasma metabolomics and biochemical analyses revealed a marked global effect of GR deficiency on systemic metabolite abundance and, thus, substrate partitioning in fed and fasted states. This correlated with a decreased lipolytic capacity of GR-deficient adipocytes under postabsorptive and fasting conditions, resulting from impaired signal transduction from ß-adrenergic receptors to adenylate cyclase. Upon prolonged fasting, the impaired lipolytic response resulted in abnormal substrate utilization and lean mass wasting. Conversely, GR deficiency attenuated aging-/diet-associated obesity, adipocyte hypertrophy, and liver steatosis. Systemic glucose tolerance was improved in obese GR-deficient mice, which was associated with increased insulin signaling in muscle and adipose tissue. We conclude that the GR in adipocytes exerts central but diverging roles in the regulation of metabolic homeostasis depending on the energetic state. The adipocyte GR is indispensable for the feeding-fasting transition but also promotes adiposity and associated metabolic disorders in fat-fed and aged mice.

Adipocyte STAT5 deficiency promotes adiposity and impairs lipid mobilisation in mice.

AIMS/HYPOTHESIS: Dysfunction of lipid metabolism in white adipose tissue can substantially interfere with health and quality of life, for example in obesity and associated metabolic diseases. Therefore, it is important to characterise pathways that regulate lipid handling in adipocytes and determine how they affect metabolic homeostasis. Components of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway are involved in adipocyte physiology and pathophysiology. However, the exact physiological importance of the STAT family member STAT5 in white adipose tissue is yet to be determined. Here, we aimed to delineate adipocyte STAT5 functions in the context of lipid metabolism in white adipose tissue. METHODS: We generated an adipocyte specific knockout of Stat5 in mice using the Adipoq-Cre recombinase transgene followed by in vivo and in vitro biochemical and molecular studies. RESULTS: Adipocyte-specific deletion of Stat5 resulted in increased adiposity, while insulin resistance and gluconeogenic capacity was decreased, indicating that glucose metabolism can be improved by interfering with adipose STAT5 function. Basal lipolysis and fasting-induced lipid mobilisation were diminished upon STAT5 deficiency, which coincided with reduced levels of the rate-limiting lipase of triacylglycerol hydrolysis, adipose triglyceride lipase (ATGL, encoded by Pnpla2) and its coactivator comparative gene identification 58 (CGI-58). In a mechanistic analysis, we identified a functional STAT5 response element within the Pnpla2 promoter, indicating that Pnpla2 is transcriptionally regulated by STAT5. CONCLUSIONS/INTERPRETATION: Our findings reveal an essential role for STAT5 in maintaining lipid homeostasis in white adipose tissue and provide a rationale for future studies into the potential of STAT5 manipulation to improve outcomes in metabolic diseases.