The deleterious effect of chronic activation of the IL-1 system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1 in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1, in a glucose-dependent manner. Subsequently, IL-1 contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1 signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1 and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1 mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium-glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1 and insulin in the regulation of both metabolism and immunity. 30reactive oxygen species production, and NLRP3 inflammasome-mediated IL-1β secretion. 31Post-prandial inflammation is limited by normalization of glycemia and can be prevented by 32 inhibition of sodium-glucose cotransporter 2 (SGLT2). Our findings identify a physiological 33 role for IL-1β and insulin in the regulation of both metabolism and immunity.

SummaryIdentifying distinct anatomical structures within the brain and developing genetic tools to target them are fundamental steps for understanding brain function. We hypothesize that enhancer expression patterns can be used to automatically identify functional units such as neuropils and fiber tracts. We used two recent, genome-scale Drosophila GAL4 libraries and associated confocal image datasets to segment large brain regions into smaller subvolumes. Our results (available at https://strawlab.org/braincode) support this hypothesis because regions with well-known anatomy, namely the antennal lobes and central complex, were automatically segmented into familiar compartments. The basis for the structural assignment is clustering of voxels based on patterns of enhancer expression. These initial clusters are agglomerated to make hierarchical predictions of structure. We applied the algorithm to central brain regions receiving input from the optic lobes. Based on the automated segmentation and manual validation, we can identify and provide promising driver lines for 11 previously identified and 14 novel types of visual projection neurons and their associated optic glomeruli. The same strategy can be used in other brain regions and likely other species, including vertebrates.

Chronic inflammation impairs insulin secretion and sensitivity. β-cell dedifferentiation has recently been proposed as a mechanism underlying β-cell failure in T2D. Yet the effect of inflammation on β-cell identity in T2D has not been studied. Therefore, we investigated whether pro-inflammatory cytokines induce β-cell dedifferentiation and whether anti-inflammatory treatments improve insulin secretion via β-cell redifferentiation. We observed that IL-1β, IL-6 and TNFα promote β-cell dedifferentiation in cultured human and mouse islets, with IL-1β being the most potent one of them. In particular, β-cell identity maintaining transcription factor Foxo1 was downregulated upon IL-1β exposure. In vivo, anti-IL-1β, anti-TNFα or NF-kB inhibiting sodium salicylate treatment improved insulin secretion of isolated islets. However, only TNFα antagonism partially prevented the loss of β-cell identity gene expression. Finally, the combination of IL-1β and TNFα antagonism improved insulin secretion of ex vivo isolated islets in a synergistic manner. Thus, while inflammation triggered β-cell dedifferentiation and dysfunction in vitro, this mechanism seems to be only partly responsible for the observed in vivo improvements in insulin secretion.