Obesity is a major health burden that elevates the risk for chronic diseases such as type 2 diabetes [1]. Hypercaloric diets overactivate the intestinal immune system and disrupt microbiome and epithelial cell functions, contributing to impaired glucose metabolism [2]. The origins of the intestinal inflammatory cascade are, however, poorly characterized. Here, we depleted pro-inflammatory group 1 innate lymphoid cells (ILC1s) in mice fed a high-fat-high-sugar diet to investigate their involvement in the progression of obesity. We found that ILC1s are required for the expansion of pro-inflammatory macrophages and ILC2s, as their blockade buffered obesity-associated intestinal inflammation. Depletion of ILC1s also induced the ILC3-IL22 pathway, leading to an increase in mucin production, antimicrobial peptide expression and neuroendocrine cell abundance. The latter explained the increase in serum levels of peptide YY, glucagon-like peptides 1 and 2, which was accompanied by a reduction of insulinemia and adiposity in ILC1-depleted mice. This coincided with a bloom of Akkermansia muciniphila, a reduction of the pathobiont Bilophila spp., and a specific metabolic shift in obese mice depleted of ILC1s. Overall, we show that intestinal epithelial ILC1s are upstream activators of inflammatory macrophages, linking immunity with the microbiome and the enteroendocrine control of glucose metabolism and adiposity. -- 1. Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: A systematic analysis for the Global Burden of Disease Study 2013. The Lancet 2014;384:766–81. doi:10.1016/S0140-6736(14)60460-8 2. Roselli M, Canali R, Finamore A, et al. Immune System, Gut Microbiota and Diet: An Interesting and Emerging Trialogue. IntechOpen 2022. doi:10.5772/intechopen.104121