Macroautophagy/autophagy is a conserved cellular self-digestive mechanism to catabolize superfluous or damaged cellular components to maintain cell homeostasis. Impaired autophagy underlies multiple pathophysiological states, including aging, neurodegenerative, inflammatory, and metabolic diseases. Intermittent fasting and caloric restriction are effective means by which to activate autophagy, yet relatively few people can sustain such intensive interventions in real-world settings. Moreover, current pharmacotherapies do not yet fully exploit autophagic flux as a target mechanism. Here, we discuss recent work, which demonstrates that arginine catabolism is a tractable process to activate autophagy with utility to treat obesity and its complications. Hepatocyte-specific transgenic activation of arginine catabolism, or systemic administration of an anti-tumor pharmacotherapy, pegylated arginine deiminase, each promote energy expenditure and insulin sensitivity, and reduce dyslipidemia and hepatic steatosis in obese mice. These effects depend upon hepatocyte Fgf21, and whole-body Becn1 expression. The data suggest that hepatocyte and systemic arginine catabolism drive autophagy, and identify an index pharmacological agent to leverage this process.