In rodent models of type 2 diabetes (T2D), sustained remission of diabetic hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1). To identify the brain areas responsible for this effect, we first used immunohistochemistry to map the hypothalamic distribution of phosphorylated extracellular signal–related kinase 1/2 (pERK1/2), a marker of mitogen-activated protein kinase–ERK signal transduction downstream of FGF receptor activation. Twenty minutes after icv FGF1 injection in adult male Wistar rats, pERK1/2 staining was detected primarily in two hypothalamic areas: the arcuate nucleus–median eminence (ARC-ME) and the paraventricular nucleus (PVN). To determine whether an action of FGF1 localized to either the ARC-ME or the PVN is capable of mimicking the sustained antidiabetic effect elicited by icv FGF1, we microinjected either saline vehicle or a low dose of FGF1 (0.3 µg/side) bilaterally into either the ARC-ME area or PVN of Zucker Diabetic Fatty rats, a model of T2D, and monitored daily food intake, body weight, and blood glucose levels over a 3-week period. Whereas bilateral intra-arcuate microinjection of saline vehicle was without effect, remission of hyperglycemia lasting >3 weeks was observed following bilateral microinjection of FGF1 into the ARC-ME. This antidiabetic effect cannot be attributed to leakage of FGF1 into cerebrospinal fluid and subsequent action on other brain areas, since icv injection of the same total dose was without effect. Combined with our finding that bilateral microinjection of the same dose of FGF1 into the PVN was without effect on glycemia or other parameters, we conclude that the ARC-ME area (but not the PVN) is a target for sustained remission of diabetic hyperglycemia induced by FGF1.
Summary In leptin-deficient ob/ob mice, obesity and diabetes are associated with abnormal development of neurocircuits in the hypothalamic arcuate nucleus (ARC) 1 , a critical brain area for energy and glucose homeostasis 2 , 3 . As this developmental defect can be remedied by systemic leptin administration, but only if given before postnatal day 28, a critical period (CP) for leptin-dependent development of ARC neurocircuits has been proposed 4 . In other brain areas, CP closure coincides with the appearance of perineuronal nets (PNNs), extracellular matrix specializations that restrict the plasticity of neurons that they enmesh 5 . Here we report that in humans as well as rodents, subsets of neurons in the mediobasal aspect of the ARC are enmeshed by PNN-like structures. In mice, these neurons are densely-packed into a continuous ring that encircles the junction of the ARC and median eminence, which facilitates exposure of ARC neurons to the circulation. Most of the enmeshed neurons are both GABAergic and leptin receptor-positive, including a majority of Agrp neurons. Postnatal formation of the PNN-like structures coincides precisely with closure of the CP for Agrp neuron maturation and is dependent on input from circulating leptin, as postnatal ob/ob mice have reduced ARC PNN-like material that is restored by leptin administration during the CP. We conclude that neurons crucial to metabolic homeostasis are enmeshed by PNN-like structures and organized into a densely packed cluster situated circumferentially at the ARC-ME junction, where metabolically-relevant humoral signals are sensed.
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