OBJECTIVEMatricellular Secreted Protein, Acidic and Rich in Cysteine (SPARC), originally discovered in bone as osteonectin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines.RESEARCH DESIGN AND METHODSSerum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 ± 3.7 kg). Another six lean subjects underwent fast-food–based hyperalimentation for 4 weeks (weight gain: 7.2 ± 1.6 kg). Finally, visceral adipose tissue explants were cultured with recombinant leptin, insulin, and glucose, and SPARC mRNA and protein expression determined by Western blot analyses.RESULTSSPARC expression in human adipose tissue correlated with fat mass and was higher in SCAT. Weight loss induced by very-low-calorie diet lowered SPARC expression by 33% and increased by 30% in adipose tissue of subjects gaining weight after a fast-food diet. SPARC expression was correlated with leptin independent of fat mass and correlated with homeostasis model assessment–insulin resistance. In vitro experiments showed that leptin and insulin potently increased SPARC production dose dependently in visceral adipose tissue explants, while glucose decreased SPARC protein.CONCLUSIONSOur data suggest that SPARC expression is predominant in subcutaneous fat and its expression and secretion in adipose tissue are influenced by fat mass, leptin, insulin, and glucose. The profibrotic effects of SPARC may contribute to metabolic dysregulation in obesity.

Objectives: To review the performance and utility of the International Academy of Cytology (IAC) Yokohama System for Reporting Breast Fine Needle Aspiration Biopsy (FNAB) Cytology five category stratification and evaluate the impact of rapid onsite evaluation (ROSE). Method: A retrospective analysis of breast FNAB cytology cases with matched histopathological results at a single institution over a 32 months period using a structured reporting system with 5 diagnostic categories (“inadequate/insufficient,” “benign,” “atypical,” “suspicious of malignancy” and “malignant”) closely paralleling the proposed IAC System. Results: Of 2,696 breast FNAB cases, there were 579 with matched histopathology and 456 of these had ROSE. ROSE decreased the number in the “insufficient” category (17.1% without ROSE to 4.0% with ROSE) and increased the number in the “malignant” (17.9 to 39.0%) with a lesser impact on the “atypical,” “benign” and “suspicious of malignancy” categories. The performance data showed a positive predictive value of 96.4%, negative predictive value of 97.6%, and a risk of malignancy of a FNAB categorized as “insufficient” to be 2.6%, “benign” 1.7%, “atypical” 15.7%, “suspicious of malignancy” 84.6%, and “malignant” 99.5%. Conclusion: Breast FNAB is an accurate test enabling effective diagnosis of breast lesions. ROSE improved the performance by decreasing the proportion of “insufficient” and “atypical” and increasing the “suspicious of malignancy” and “malignant” diagnoses and enabling immediate triage for further biopsy where necessary.

Many patients with diabetes mellitus (both type 1 and type 2) require therapy to maintain normal fasting glucose levels. To develop a novel treatment for these individuals, we used phage display technology to target the insulin receptor (INSR) complexed with insulin and identified a high affinity, allosteric, human monoclonal antibody, XMetA, which mimicked the glucoregulatory, but not the mitogenic, actions of insulin. Biophysical studies with cultured cells expressing human INSR demonstrated that XMetA acted allosterically and did not compete with insulin for binding to its receptor. XMetA was found to function as a specific partial agonist of INSR, eliciting tyrosine phosphorylation of INSR but not the IGF-IR. Although this antibody activated metabolic signaling, leading to enhanced glucose uptake, it neither activated Erk nor induced proliferation of cancer cells. In an insulin resistant, insulinopenic model of diabetes, XMetA markedly reduced elevated fasting blood glucose and normalized glucose tolerance. After 6 weeks, significant improvements in HbA1c, dyslipidemia, and other manifestations of diabetes were observed. It is noteworthy that hypoglycemia and weight gain were not observed during these studies. These studies indicate, therefore, that allosteric monoclonal antibodies have the potential to be novel, ultra-long acting, agents for the regulation of hyperglycemia in diabetes.

Objective: To investigate a potential role for obestatin in humans by examining response to a fixed energy meal. Context: A new anorectic peptide hormone, obestatin has recently been isolated from rat stomach. The significance of this peptide in humans is unknown. Study design: Case-control study. Setting: Hospital-based study. Patients: Nine healthy controls, nine morbidly obese subjects and eight post-gastrectomy subjects. Intervention: Subjects attended after an overnight fast and were given a fixed energy meal (1550 kJ). Main outcome measure: The response of obestatin to a meal in the different groups. Results: Fasting obestatin was significantly lower in obese subjects as compared to lean subjects (27.874 vs 17.272 pg/ml, P ¼ 0.03). Obestatin was also decreased in gastrectomy subjects but this did not reach statistical significance (27.874 vs 21.973 pg/ml, P ¼ 0.3). Obestatin did not change significantly from baseline in response to the meal. Lean and obese subjects had a similar obestatin/ghrelin ratio (0.0470.003 vs 0.0570.009, P ¼ 0.32), but this was higher in the gastrectomy group (0.0470.003 vs 0.170.01, Po0.001). Conclusions: Obestatin does not vary significantly with a fixed energy meal, but is significantly lower in morbidly obese subjects as compared to lean subjects supporting a possible role for obestatin in long-term body weight regulation. Obestatin tended to be lower in gastrectomy subjects and their obestatin/ghrelin ratio differed from healthy controls. Hence, the expression of obestatin is altered following gastrectomy, suggesting other sites outside the stomach may also secrete obestatin.

Immune activation occurs in response to noxious stimuli such tissue injury, infection, inflammation and malignant neoplasia with the production of cytokines both in the circulation and the central nervous system (CNS). In addition to their fundamental immune functions, cytokines such as the interleukins (ILs), interferons (IFNs) and tumour necrosis factor-alpha also elicit significant pathophysiological effects on feeding behaviour and play prominent roles in the anorexia and cachexia syndrome often seen in chronic disease states. There is now compelling evidence that demonstrates that an important site of cytokine bioactivity is located within the hypothalamus where they appear to modulate appetite and energy homeostasis. Hypercytokinaemia has also been observed in the obese state where it has been proposed that they may play pivotal roles in mediating the detrimental components of the metabolic syndrome including insulin resistance, impaired glucose tolerance, hypertension. dyslipidaemia and increased cardiovascular risk. This review summarises these putative roles of various cytokines in the regulation of feeding in the setting of anorexia-cachexia and obesity.

Objective: To examine the effects of ghrelin on appetite and energy expenditure in lean, obese and postgastrectomy subjects. Design: A randomized, double-blind, placebo-controlled study. Patients: Nine lean subjects (mean body mass index (BMI) 23.5±3 kg/m 2 ) and nine morbidly obese subjects (mean BMI 51.4 ± 10 kg/m 2 ) and eight postgastrectomy subjects (mean BMI 22.4 ± 1.0 kg/m 2 ). Interventions: Subjects were infused with either intravenous ghrelin (5 pmol kg À1 min À1 ) or saline over 270 min. They were given a fixed energy breakfast followed by a free buffet lunch towards the end of the infusion. Main outcome measures: Visual analogue scales were used to record hunger and energy expenditure was measured by indirect calorimetry. Results: Ghrelin increased energy intake at the buffet lunch in lean subjects (a 41% increase, Po0.01) and obese subjects (35% increase, P ¼ 0.04) but not in postgastrectomy subjects. Lean subjects showed a characteristic preprandial rise and postprandial fall in hunger scores, which was exaggerated by ghrelin infusion. Obese subjects showed little variation in hunger scores, but a 'lean-type' pattern was restored when given exogenous ghrelin. Ghrelin had no effect on resting metabolic rate but did increase respiratory quotient (RQ) in obese subjects. Ghrelin also increased RQ variability over time in all three groups (ANOVA, Po0.001). Conclusions: Hunger scores are abnormal in the obese, perhaps because of impaired ghrelin secretion. The effect of ghrelin in restoring normal hunger profiles in the obese suggests causality, confirming an important role in eating behaviour. Ghrelin also increases RQ in obese humans and increased RQ variability in all groups. This suggests that ghrelin regulates substrate utilization and may promote metabolic flexibility.

Objective: The clinical utility and prognostic value of WHO 2017 lineage-based classification of pituitary tumours have not been assessed. This study aimed to (1) determine the clinical utility of transcription factor analysis for classification of pituitary tumours and (2) determine the prognostic value of improved lineage-based classification of pituitary tumours. Methods: This was a retrospective evaluation of patients who underwent surgical resection of pituitary tumours at St Vincent’s Public and Private Hospitals, Sydney, Australia between 1990 and 2016. Included patients were at least 18 years of age and had complete histopathological data, forming the “histological cohort”. Patients with at least 12 months of post-surgical follow up were included in the subgroup “clinical cohort”. The diagnostic efficacy of transcription factor immunohistochemistry in conjunction with hormone immunohistochemistry was compared with hormone immunohistochemistry alone. The prognostic value of identifying “higher risk” histological subtypes was assessed. Results: There were 171 patient tumour samples analyzed in the histological cohort. Of these, there were 95 patients forming the clinical cohort. Subtype diagnosis was changed in 20/171 (12%) of tumours. Within the clinical cohort, there were 21/95 (22%) patients identified with higher risk histological subtype tumours. These were associated with tumour invasiveness (p=0.050), early recurrence (12-24 months, p=0.013), shorter median time to recurrence (49 [IQR 22.5-73.0] v 15 [IQR 12.0-25.0] months, p=0.005) and reduced recurrence-free survival (p=0.031). Conclusions: Application of transcription factor analysis, in addition to hormone immunohistochemistry, allows for refined pituitary tumour classification and may facilitate an improved approach to prognostication.

AT-derived RBP4-mRNA expression is gender specific and regulated by leptin. Circulating RBP4 levels appear to be independent of AT-RBP4 secretion.