Objective: Ethnic differences in fat deposition contribute to type 2 diabetes (T2D). Identification of biomarkers that underpin dysglycemia are needed for better-targeted prevention and treatment. Methods: The cross-sectional thin-on-the-outside-faton-the-inside (TOFI)_Asia study investigated adipose depots and clinical biomarkers as predictors of fasting plasma glucose (FPG) and insulin resistance (IR; assessed using the updated homeostatic model assessment of IR) in lean and overweight normo-and dysglycemic Chinese (n = 199) and Caucasian (n = 158) individuals. Multivariate least-angle regression models were used to identify predictors of FPG and IR. Results: At similar age and BMI, Chinese individuals had lower body weight but had a greater percentage of total abdominal adipose tissue and a greater percentage of total visceral adipose tissue (VAT) (all P < 0.005). In Chinese individuals, FPG, hemoglobin A 1c , fasting insulin, and triglycerides were higher, whereas HDL cholesterol and total and high-molecular-weight adiponectin levels were lower (all P < 0.0001). Raised liver enzyme and peptide concentrations (P < 0.02) were consistent with increased T2D risk. Lean Chinese women (<25 kg/m 2) had greater total abdominal adipose tissue (kilograms) and VAT (kilograms) than Caucasian women, exhibiting the TOFI profile, with raised FPG (P < 0.001) and IR (P = 0.01). Risk factors for elevated FPG specific to Chinese individuals included male gender, VAT, and triglycerides (R 2 = 0.33), and risk factors for IR specific to Chinese individuals included amylin, C-peptide, and glucagon (R 2 = 0.49). VAT, amylin, and C-peptide were predictors in Caucasian individuals.

Signaling through calcitonin gene-related peptide (CGRP) receptors is associated with pain, migraine, and energy expenditure. Small molecule and monoclonal antibody CGRP receptor antagonists that block endogenous CGRP action are in clinical use as anti-migraine therapies. By comparison, the potential utility of peptide antagonists has received less attention due to suboptimal pharmacokinetic properties. Lipidation is an established strategy to increase peptide half-life in vivo. This study aimed to explore the feasibility of developing lipidated CGRP peptide antagonists that retain receptor antagonist activity in vitro and attenuate endogenous CGRP action in vivo. CGRP peptide analogues based on the archetypal CGRP receptor antagonist, CGRP8-37, were palmitoylated at the N-terminus, position 24, and near the C-terminus at position 35. The antagonist activities of the lipidated peptide analogues were tested in vitro using transfected Cos-7 cells expressing either the human or mouse CGRP receptor, amylin subtype 1 (AMY1) receptor, adrenomedullin (AM) receptors, or calcitonin receptor. Antagonist activities were also evaluated in SK-N-MC cells that endogenously express the human CGRP receptor. Lipidated peptides were then tested for their ability to antagonize endogenous CGRP action in vivo using a capsaicin-induced dermal vasodilation (CIDV) model in C57/BL6J mice. All lipidated peptides except for the C-terminally modified analogue retained potent antagonist activity compared to CGRP8-37 towards the CGRP receptor. The lipidated peptides also retained, and sometimes gained, antagonist activities at AMY1, AM1 and AM2 receptors. Several lipidated peptides produced robust inhibition of CIDV in mice. This study demonstrates that selected lipidated peptide antagonists based on αCGRP8-37 retain potent antagonist activity at the CGRP receptor and are capable of inhibition of endogenous CGRP action in vivo. These findings suggest that lipidation can be applied to peptide antagonists, such as αCGRP8-37 and are a potential strategy for antagonizing CGRP action.

This study aimed to identify behaviours that could be used to assess post-operative pain and analgesic efficacy in male rabbits. In consideration of the ‘Three Rs’, behavioural data were collected on seven male New Zealand White rabbits in an ethically approved experiment requiring abdominal implantation of a telemetric device for purposes other than behavioural assessment. Prior to surgery, rabbits were anaesthetised using an isoflurane/oxygen mix and given Carprofen (2 mg kg−1) as a peri-operative analgesic. Rabbits were housed individually in standard laboratory cages throughout. Data were collected at three time periods: 24-21 h prior to surgery (T1) and, post-surgery, 0-3 h (T2) and 3-6 h (T3). Behavioural changes were identified using Observer XT, significance of which was assessed using a Friedman's test for several related samples. The frequency or duration of numerous pre-operative behaviours was significantly reduced in T2 and T3, as compared to T1. Conversely, novel or rare behaviours had either first occurrence or significant increase in T2 into T3 as compared to T1, these include ‘full-body-flexing’, ‘tight-huddling’, ‘hind-leg-shuffling’. We conclude that reduced expression of common pre-operative behaviours and the appearance of certain novel post-operative behaviours may be indicative of pain in rabbits. Behaviours identified as increased in T2 as compared to T1 but not consistently elevated into T3 were considered separately due to the potentially confounding effect of anaesthesia recovery. These included lateral lying, ‘drawing-back’, ‘staggering’ and ‘closed eyes’. We postulate that for effective application of best-practice post-operative care, informed behavioural observation can provide routes by which carers may identify requirements for additional post-operative analgesia. Additionally, improvement of the peri-operative pain management regimen may be required to ameliorate the immediate effects of abdominal surgery. Comparisons with other studies into post-operative pain expression in rabbits suggest behavioural indicators of pain may differ, depending on housing and surgical procedure.

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Background Bimatoprost negatively regulates adipogenesis in vitro and likely participates in a negative feedback loop on anandamide-induced adipogenesis. Here, we investigate the broader metabolic effects of bimatoprost action in vivo in rats under both normal state and obesity-inducing conditions. Methods Male Sprague Dawley rats were a fed standard chow (SC) diet in conjunction with dermally applied bimatoprost treatment for a period of 9–10 weeks. Body weight gain, energy expenditure, food intake, and hormones associated with satiety were measured. Gastric emptying was also separately evaluated. In obesity-promoting diet studies, rats were fed a cafeteria diet (CAF) and gross weight, fat accumulation in SQ, visceral fat and liver was evaluated together with standard serum chemistry. Results Chronic bimatoprost administration attenuated weight gain in rats fed either standard or obesity-promoting diets over a 9–10 weeks. Bimatoprost increased satiety as measured by decreased food intake, gastric emptying and circulating gut hormone levels. Additionally, SQ and visceral fat mass was distinctly affected by treatment. Bimatoprost increased satiety as measured by decreased food intake, gastric emptying and circulating gut hormone levels. Conclusions These findings suggest that bimatoprost (and possibly prostamide F2α) regulates energy homeostasis through actions on dietary intake. These actions likely counteract the metabolic actions of anandamide through the endocannabinoid system potentially revealing a new pathway that could be exploited for therapeutic development.