1823-P: Evidence that Arcuate Nucleus Neurocircuit Remodeling Ameliorates Hyperglycemia in Type 2 Diabetes

Abstract

Abnormal development of neurocircuits in the hypothalamic arcuate nucleus (ARC) is a common feature of genetic and acquired (e.g., postnatal overnutrition) models of obesity and type 2 diabetes (T2D). In leptin-deficient ob/ob mice, developmental defects occur both in efferent projections from the ARC to downstream circuits and in afferent GABAergic input onto ARC neurons. A developmental critical period (CP) has been proposed based on the temporally-restricted requirement for leptin, during the first month of life, to enable normal projections of ARC Agrp neurons in ob/ob mice. We recently described the formation of perineuronal nets (PNNs) around ARC Agrp neurons during the latter half of this CP, shortly following the peak of the postnatal leptin surge. PNNs, which are extracellular matrix specializations that restrict CP plasticity in neurons they enmesh, were overabundant in the ARC of adult ob/ob mice, suggesting that ARC neurocircuit dysfunction contributes to their metabolic phenotype. To remodel ARC neurocircuits containing PNN-enmeshed cells, we engrafted a special population of GABAergic inhibitory interneurons derived from the embryonic brain medial ganglionic eminence (MGE). Here we show that MGE interneurons derived from E13.5 GAD67-GFP embyros and transplanted bilaterally into the ob/ob ARC survive, integrate into local circuits, and form GABAergic synapses. Preliminary metabolic phenotyping shows that compared to vehicle injection, transplanted MGE cells (∼5000 MGE cells/ARC) induce a sustained reduction of hyperglycemia lasting for at least one month (1-month average BG: veh 301±12 vs. MGE 189±12 mg/dl, n=4/group, p=0.022) without significant effects on food intake or body weight. These findings suggest that sustained diabetes remission can be achieved by remodeling ARC neurocircuits through MGE cell transplantation. Disclosure Z. Mirzadeh: Consultant; Self; Novo Nordisk A/S. E. Cabrales: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Funding National Institute of Neurological Disorders and Stroke