Inflammation has a critical role in the development of insulin resistance. Recent evidence points to a contribution by the central nervous system in the modulation of peripheral inflammation through the anti-inflammatory reflex. However, the importance of this phenomenon remains elusive in type 2 diabetes pathogenesis. Here we show that rat insulin-2 promoter (Rip)-mediated deletion of Pten, a gene encoding a negative regulator of PI3K signaling, led to activation of the cholinergic anti-inflammatory pathway that is mediated by M2 activated macrophages in peripheral tissues. As such, Rip-cre⁺Pten^flox/flox mice showed lower systemic inflammation and greater insulin sensitivity under basal conditions compared to littermate controls, which were abolished when the mice were treated with an acetylcholine receptor antagonist or when macrophages were depleted. After feeding with a high-fat diet, the Pten-deleted mice remained markedly insulin sensitive, which correlated with massive subcutaneous fat expansion. They also exhibited more adipogenesis with M2 macrophage infiltration, both of which were abolished after disruption of the anti-inflammatory efferent pathway by left vagotomy. In summary, we show that Pten expression in Rip⁺ neurons has a critical role in diabetes pathogenesis through mediating the anti-inflammatory reflex.