TL1A regulates adipose-resident innate lymphoid immune responses and enables diet-induced obesity in mice.

BACKGROUND/OBJECTIVES: TL1A is a pro-inflammatory cytokine that is homologous to TNFα and connected with the development of several chronic inflammatory disorders. The preliminary results of this study indicated reduced fat accumulation in 9-month-old TL1A-deficient mice at steady state. Thus, the objective was to investigate whether TL1A-deficient mice are resistant to the development of high-fat (HF) diet-induced obesity and to investigate the impact on lymphocyte infiltration in adipose tissue. METHODS: TL1A-deficient and TL1A-sufficient male BALB/cJ littermate mice were fed a 60% HF diet or a 10% low-fat control diet for 22 weeks. Mouse body composition and weight were monitored, and tissues were processed and evaluated by flow cytometry, qPCR, and histology. RESULTS: In this study, the TL1A-deficient HF-diet-fed mice had reduced whole-body weight gain, which was directly explained by a corresponding fat mass reduction (average 37.2%), compared with that of their TL1A-sufficient littermates. Despite previous data showing marked changes in the gut microbial community, TL1A-deficient GF mice also displayed reduced adiposity. Furthermore, the TL1A-deficient mice were resistant to hepatic steatosis and were shown to have improved glucose tolerance, as determined by oral glucose tolerance test (OGTT), and greater insulin sensitivity. In the epididymal white adipose tissue (eWAT), TL1A deficiency in HF-diet-fed mice resulted in a reduced abundance of IL-18Ra+ type-1 ILCs and γδT cells as well as markedly reduced expression of the mitochondria-regulating genes Ucp1, Ucp2, Ucp3, and Prdm16. Finally, to investigate the link of TL1A to obesity in humans, we identified a noncoding polymorphism (rs4979453) close to the TL1A locus that is associated with waist circumference in men (p = 0.00096, n = 60586). CONCLUSIONS: These findings indicate that TL1A plays an important role in regulating adipose tissue mass and that this role is independent of the gut microbiota. Furthermore, we show that TL1A regulates adipose-resident innate lymphocytes and mitochondria-mediated oxidative stress in eWAT.

Are independent agricultural advisors more oriented towards recommending reduced pesticide use than supplier-affiliated advisors?

This paper explores whether agricultural advisors employed by chemical companies or agricultural companies selling pesticides (supplier-affiliated advisors) are more likely to recommend more intensive use of pesticides than advisors employed by companies without an economic interest in selling pesticides (independent advisors). We further test whether potential differences in advice are caused by differences in advisors' perceived demands for advice from farmers, different environmental risk perceptions about pesticide use or different weighing of the purposes of pesticide use. The analysis is based on a survey administered to the whole population of 540 advisors in Denmark; we received 227 valid responses. The main finding is that pesticide advice differs across company type. We find that supplier-affiliated advisors are less likely to recommend lower doses - scoring on average 3.9 on a scale from 1 (never) to 5 (always). Independent advisors employed at Danish Agricultural Advisory Services score an average of 4.3. The difference is statistically significant. The analysis does not offer strong support for the different causal mediators we examined. Advisors across company type tend to weigh different objectives equally; tend to agree on environmental risk perception of using pesticides; and differ only slightly on perceived farmer demand. One possible conclusion, therefore, is that explanation is as simply that differences in economic incentives produce different recommendations between advisory companies. Policy implications of the findings are that the European Union should consider addressing this difference more directly when regulating the use of pesticides in European agriculture through e.g. the Sustainable Use of Pesticides Directive (Directive, 2009/128/EC). More differentiation in the approaches for informing different types of advisors might be needed. Moreover, our results point towards the need for knowledge about whether advisors in other countries than Denmark tend to believe that approved pesticides are innocuous to the environment because such perceptions might hamper initiatives to reduce the doses of approved pesticides.

TL1A Aggravates Cytokine-Induced Acute Gut Inflammation and Potentiates Infiltration of Intraepithelial Natural Killer Cells in Mice.

BACKGROUND: The tumor necrosis factor alpha (TNFα)-homologous cytokine TL1A is emerging as a major player in intestinal inflammation. From in vitro experiments on human lymphocytes, TNF-like molecule 1A (TL1A) is known to activate a highly inflammatory lymphoid response in synergy with interleukin (IL)-12 and IL-18. Carriers of specific genetic polymorphisms associated with IL-12, IL-18, or TL1A signaling have increased Crohn's disease risk, and all 3 cytokines are upregulated during active disease. The study aim was to investigate whether the type 1-polarizing cytokines IL-12 and IL-18 could directly initiate intestinal pathology in mice and how TL1A would influence the resulting inflammatory response. METHODS: Conventional barrier-bred and germ-free mice were randomly allocated to different groups and injected twice with different combinations of IL-12, IL-18, and TL1A, and killed 3 days after the first injection. All treatment groups were co-housed and fed a piroxicam-supplemented chow diet. RESULTS: Intestinal pathology was evident in IL-12- and IL-18-treated mice and highly exacerbated by TL1A in both the colon and ileum. The cytokine-induced intestinal inflammation was characterized by epithelial damage, increased colonic levels of TNFα, IL-1ß, IFN-γ, and IL-6, and various chemokines along with gut microbiota alterations exhibiting high abundance of Enterobacteriaceae. Furthermore, the inflamed ileum and colon exhibited a TL1A-specific increased infiltration of intraepithelial natural killer cells co-expressing NKG2D and IL-18Ra and a higher frequency of unconventional T cells in the colonic epithelium. Upon cytokine injection, germ-free mice exhibited similar intraepithelial lymphoid infiltration and increased colonic levels of IFNγ and TNFα. CONCLUSIONS: This study demonstrates that TL1A aggravates IL-12- and IL-18-induced intestinal inflammation in the presence and absence of microbiota.