While an over-simplification, AMP-activated protein kinase (AMPK) generally promotes catabolic and mechanistic target of rapamycin complex 1 (mTORC1) initiates anabolic programs. The yin-yang/reciprocal nature of these pathways has been exquisitely uncovered over the past 20 years and holds true across millions of years of evolution. Moreover, the regulatory networks controlled by AMPK and mTORC1 are vast and in many cases, cell-type specific. Conclusions continue to be drawn based on phosphorylation status of their downstream targets (an arguably passive readout). While genetic knockout models have been an invaluable tool toward understanding biological function and significance in health and disease, point mutant mice, where specific targets sites are mutated are necessary to unambiguously dissect the role of individual signaling axes. As a collaborative effort, we set out to determine the importance of AMPK-mediated mTORC1 inhibition by using knock-in (KI) mice that have Ser-Ala mutations at both AMPK sites on Raptor (722/792) and newly generated mice harbouring Ser-Ala mutation on Tsc2 (1387), which when crossed together (all 3 sites abolished), represent a model that lacks two of the most well-described regulatory inputs controlling mTORC1. We have endeavoured to clarify and uncover the physiological significance of AMPK-mediated signaling through these regulators in the context of diet-induced obesity, hepatic lipid metabolism and macrophage immunometabolism.