Obesity has become a major health problem in the industrialized world. Immune regulation plays an important role in adipose tissue homeostasis; however, the initial events that shift the balance from a noninflammatory homeostatic environment toward inflammation leading to obesity are poorly understood. Here, we report a role for the costimulatory molecule programmed death-ligand 1 (PD-L1) in the limitation of diet-induced obesity. Functional ablation of PD-L1 on dendritic cells (DCs) using conditional knockout mice increased weight gain and metabolic syndrome during diet-induced obesity, whereas PD-L1 expression on type 2 innate lymphoid cells (ILC2s), T cells, and macrophages was dispensable for obesity control. Using in vitro cocultures, DCs interacted with T cells and ILC2s via the PD-L1:PD-1 axis to inhibit T helper type 1 proliferation and promote type 2 polarization, respectively. A role for PD-L1 in adipose tissue regulation was also shown in humans, with a positive correlation between PD-L1 expression in visceral fat of people with obesity and elevated body weight. Thus, we define a mechanism of adipose tissue homeostasis controlled by the expression of PD-L1 by DCs, which may be a clinically relevant finding with regard to immune-related adverse events during immune checkpoint inhibitor therapy.

The published reviews of novel therapies in chronic airways disease. 1 There is a potentially novel role for glucagon-like peptide 1 (GLP-1) agonists in obesity-related, metabolic asthma, though clinical trial data are lacking. 2 On the basis of work with other inflammatory states, we hypothesised that clinically-indicated use of GLP-1 agonists for glycaemic control in type 2 diabetes mellitus (T2DM) would be safe in those with concomitant asthma, potentially leading to im-proved asthma control and fewer asthma exacerbations. 3 In a pilot observational cohort study, we prospectively identified nine patients with pulmonologist-diagnosed asthma (never-smokers) and concomitant T2DM who were about to be initiated on clinically-indicated liraglutide for T2DM in the course of routine clinical care, and assessed them for asthma-related indices at baseline and 52weeks after initiating liraglutide. All received routine asthma care. Baseline characteristics of the study cohort are as shown (Table 1). Seven of the nine subjects who

CONTEXTTissue cortisol exposure is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). 11β-HSD1 in vivo, acts as an oxoreductase converting inactive cortisone to active cortisol. We hypothesized that 11β-HSD1 activity is dysregulated in obesity and alters following bariatric surgery induced weight loss in different tissues.METHODSWe recruited 21 patients prior to undergoing bariatric surgery and performed cortisol generation profiles (following oral cortisone administration), urinary corticosteroid metabolite analysis, adipose tissue microdialysis, and tissue gene expression before and after weight loss, following bariatric surgery. Archived tissue samples from 20 previous bariatric surgery patients were also used for tissue gene expression studies.RESULTSGene expression showed a positive correlation with 11β-HSD1 and BMI in omental adipose tissue (OM) (r = +0.52, P = .0001) but not sc adipose tissue (r = +0.28, P = .17). 11β-HSD1 expression in liver negatively correlated with body mass index (BMI) (r = -0.37, P = .04). 11β-HSD1 expression in sc adipose tissue was significantly reduced after weight loss (0.41 ± 0.28 vs 0.17 ± 0.1 arbitrary units, P = .02). Following weight loss, serum cortisol generation increased during a cortisol generation profile (area under the curve 26 768 ± 16 880 vs 47 579 ± 16 086 nmol/L/minute, P ≤ .0001.) Urinary corticosteroid metabolites demonstrated a significant reduction in total cortisol metabolites after bariatric surgery (15 224 ± 6595 vs 8814 ± 4824 μg/24 h, P = .01). Microdialysis of sc adipose tissue showed a threefold reduction in cortisol/cortisone ratio after weight loss.CONCLUSIONSThis study highlights the differences in tissue specific regulation of cortisol metabolism in obesity and after weight loss. Following bariatric surgery hepatic 11β-HSD1 activity increases, sc adipose tissue 11β-HSD1 activity is reduced and total urinary cortisol metabolites are reduced indicating a possible reduction in hypothalamic pituitary adrenal axis drive. 11β-HSD1 expression correlates positively with BMI in omental adipose tissue and negatively within hepatic tissue. 11β-HSD1 expression is reduced in sc adipose tissue after weight loss.

Dendritic cells (DCs) are key immune sentinels linking the innate and adaptive immune systems. DCs recognise danger signals and initiate T-cell tolerance, memory and polarisation. They are critical cells in responding to a viral illness. Obese individuals have been shown to have an impaired response to vaccinations against virally mediated conditions and to have an increased susceptibility to multi-organ failure in response to viral illness. We investigated if DCs are altered in an obese cohort (mean body mass index 51.7±7.3 kg m−2), ultimately resulting in differential T-cell responses. Circulating DCs were found to be significantly decreased in the obese compared with the lean cohort (0.82% vs 2.53%). Following Toll-like receptor stimulation, compared with lean controls, DCs generated from the obese cohort upregulated significantly less CD83 (40% vs 17% mean fluorescence intensity), a molecule implicated in the elicitation of T-cell responses, particularly viral responses. Obese DCs produced twofold more of the immunosuppressive cytokine interleukin (IL)-10 than lean controls, and in turn stimulated fourfold more IL-4-production from allogenic naive T cells. We conclude that obesity negatively impacts the ability of DCs to mature and elicit appropriate T-cell responses to a general stimulus. This may contribute to the increased susceptibility to viral infection observed in severe obesity.

The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKT cells.We measured circulating and psoriatic plaque iNKT cell numbers in two patients with type 2 diabetes and psoriasis before and after commencing GLP-1 analogue therapy. In addition, we investigated the in vitro effects of GLP-1 on iNKT cells and looked for a functional GLP-1 receptor on these cells.The Psoriasis Area and Severity Index improved in both patients following 6 weeks of GLP-1 analogue therapy. This was associated with an alteration in iNKT cell number, with an increased number in the circulation and a decreased number in psoriatic plaques. The GLP-1 receptor was expressed on iNKT cells, and GLP-1 induced a dose-dependent inhibition of iNKT cell cytokine secretion, but not cytolytic degranulation in vitro.The clinical effect observed and the direct interaction between GLP-1 and the immune system raise the possibility of therapeutic applications for GLP-1 in inflammatory conditions such as psoriasis.