Faststone capture 912/31/2022 Heightened glucagon action has been suggested to be essential 8, which is later suggested to be dependent on insulin action 9. For brain leptin action on reducing glucose in T1D, a role for β-adrenergic receptor-mediated sympathetic nerve output has been ruled out 6, 7. The CRR includes glucagon, HPA axis, and sympathetic nerve output, representing a major physiological response against hypoglycemic for glucose homeostasis, but is aberrantly activated in T1D. It is generally accepted that brain leptin action on reducing T1D hyperglycemia is mediated by suppressing counter-regulatory responses (CRR) 5. Notably, leptin action in the brain alone is sufficient to restore euglycemia in T1D, while its action in the liver is not required 3, 4. Emerging studies have demonstrated that, in addition to its role in body weight regulation, adipocyte-derived leptin is capable of reducing T1D hyperglycemia in an insulin-independent manner 1, 2. Patients with type 1 diabetes (T1D) suffer greatly from uncontrolled hyperglycemia, and insulin delivery remains the only treatment option, but is accompanied with obesity development and life-threatening hypoglycemia. Our results identify aberrant activation of LepR Arc neurons owing to energy deprivation as the neural basis for T1D hyperglycemia and that leptin action is mediated by inhibiting LepR Arc neurons through reversing energy deprivation. Finally, T1D LepR Arc neurons show defective nutrient sensing and signs of cellular energy deprivation, which are both restored by leptin, whereas nutrient deprivation reverses the leptin action. Further, AgRP neuron function is not required for T1D hyperglycemia or leptin’s rescuing effects. Conversely, inhibition of GABA Arc neurons, but not AgRP neurons, produces leptin-mimicking rescuing effects. Activation of LepR Arc neurons, Arc GABAergic (GABA Arc) neurons, or arcuate AgRP neurons, is able to reverse the leptin’s rescuing effect. Here, we show that leptin receptor (LepR)-expressing neurons in arcuate (LepR Arc) are selectively activated in T1D. Central leptin action rescues type 1 diabetic (T1D) hyperglycemia however, the underlying mechanism and the identity of mediating neurons remain elusive.
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