The survival of all cells is dependent on the constant challenge to match energetic demands with nutrient availability, a task which is mediated through a highly conserved network of metabolic fuel sensors that orchestrate both cellular and whole organism energy balance. A mismatch between cellular energy demand and nutrient availability is a key factor contributing to the development of obesity, thus understanding the fundamental mechanisms by which cells sense nutrient availability and demand may lead to the development of new treatments. Glucose lowering therapies such as caloric restriction, exercise, metformin and cold all induce an energetic challenge that results in the activation of the cellular energy sensor AMP-activated protein kinase (AMPK). Activation of AMPK in turn suppresses lipid synthesis and inflammation while increasing glucose uptake, fatty acid oxidation and mitochondrial function. In contrast, high levels of nutrient availability, suppress AMPK activity while also increasing the production of peripheral serotonin, a gut-derived endocrine factor which suppresses beta-adrenergic-induced activation of brown adipose tissue. Identifying new ways to manipulate these two ancient fuel gauges, by activating AMPK and inhibiting peripheral serotonin, may lead to the development of new therapies for treating obesity.