(A) Under fed conditions, fuel mobilization is inhibited both by the action of leptin in the brain and by the inhibitory effect of insulin (secreted by pancreatic β cells) on liver and adipose tissue. HPA, hypothalamic-pituitary-adrenal; GH, growth hormone. (B–D) In the fasted state (B), low leptin levels trigger multiple neuroendocrine and autonomic mechanisms (secretion of glucagon, increased sympathetic outflow) to promote mobilization of fuels — primarily, glucose and ketones from the liver and FFAs and glycerol from adipose tissue. These responses are constrained by insulin. In T1D (C), severe insulin deficiency causes leptin deficiency and eliminates the normal brake on fuel mobilization. Brain perception of fuel depletion therefore triggers fuel mobilization that is unopposed by either the central action of leptin or the peripheral action of insulin, leading to progressive hyperglycemia and DKA. By blocking the perception of fuel deficiency, leptin delivery directly into the brain (D) restores circulating fuel levels to normal, despite ongoing, severe insulin deficiency.