Obesity is closely associated with adipose tissue inflammation and insulin resistance. Dysglycemia and type 2 diabetes results when islet β cells fail to maintain appropriate insulin secretion in the face of insulin resistance. To clarify the early transcriptional events leading to β-cell failure in the setting of obesity, we fed male C57BL/6J mice an obesogenic, high fat diet (60% kcal from fat) or control diet (10% kcal from fat) for one week and islets from these mice (from 4 high fat- and 3 control-fed mice) were subjected to single cell RNA sequencing analysis. Islet endocrine cell types (α cells, β cells, δ cells, PP cells) and other resident cell types (macrophages, T cells) were annotated by transcript profiles and visualized using Uniform Manifold Approximation and Projection for Dimension Reduction (UMAP) plots. UMAP analysis revealed distinct cell sub-populations (11 for β cells, 5 for α cells, 3 for δ cells, PP cells, ductal cells, endothelial cells), emphasizing the heterogeneity of cell populations in the islet. We identified that distinct β cell populations downregulate genes associated with the endoplasmic reticulum stress response and upregulate genes associated with insulin secretion, while others upregulate genes that impair insulin secretion, cellular proliferation, and survival. Moreover, all β cell populations negatively regulate genes associated with immune response activation. Our data indicate that an early transcriptional response in islets to an obesogenic diet reflects an attempt by distinct populations of β cells to augment or impair cellular function, possible harbingers of ensuing insulin resistance.  Overall design: Islet isolation. Male C57BL/6J mouse pancreas were isolated from 8 weeks of age, animals were fed either a LFD (10% kcal from fat; Research Diets D12450B), or HFD (60% kcal from fat; Research Diets D12492) for one week. Islets were isolated from collagenase-perfused pancreata as previously described (Stull, 2017). After isolation, mouse islets were handpicked and digested with Accutase (EMD Millipore Corporation) containing 2U/ml of DNAse during 5min at 37°C sob agitation (1000rpm). Digested cell islets were washed several times with PBS+2%FBS to eliminate DNAse and then filtered using a cell strainer (40mm). Single cells suspension and samples with more than 90% viability were used for scRNAseq.