Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission

Abstract

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

“…While mechanisms underlying the sustained glucoselowering action of FGF1 in the MBH await additional study, our recent work points to a role for glia-neuron interactions [55] and associations with FGF1-induced changes in the extracellular matrix [56]. Whatever the mechanism, the data collectively suggest that in rodent models of type 2 diabetes, hyperglycaemia arises from pathological processes that can be corrected (or overridden) through the hypothalamic action of FGF1.…”

Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

“…Based on previous work showing that tanycytes and astrocytes are especially responsive to the effect of icv FGF1 injection to induce sustained ERK1/2 signaling 5,7 , we next examined the response of these cell types following icv injection of FGF1 R50E. As anticipated, we observed that compared to icv injection of native FGF1, pERK1/2 induction in both tanycytes (Figure 3B) and astrocytes (Figure 3C) was markedly reduced at the 14h time point after icv injection of FGF1 R50E.…”

“…The interpretation of findings reported herein is also informed by recent work that has shed light on how the hypothalamus responds to FGF1. For example, intact hypothalamic melanocortin signaling (determined by interactions between Agrp and Pomc neurons in the ARC) appears to be required for sustained glucose lowering induced by icv FGF1 injection, but is dispensable for acute, transient effects of FGF1 on food intake, body weight, and glycemia 7 . In light of our current findings, this work suggests that diabetes remission induced by icv FGF1 involves a MAPK/ERK-dependent mechanism for enhanced melanocortin signaling.…”

“…Previous work demonstrates that MAPK/ERK signaling is rapidly induced in the hypothalamus of diabetic mice by FGF19, a member of the endocrine FGF family, and that this ERK activation is required for its transient glucose-lowering action 10 . Activation of ERK signaling in the MBH has also been documented following icv administration of FGF1 and is associated with robust transcriptional changes related to the ERK pathway in both tanycytes and astrocytes 5,7 . However, neither the role played by ERK signaling in these responses nor the extent to which they contribute to the sustained antidiabetic effect of icv FGF1 is known.…”

“…Since the effect of icv FGF1 administration to normalize diabetic hyperglycemia in a sustained manner is recapitulated by microinjection of a lower dose of FGF1 directly into mediobasal hypothalamus (MBH), this brain area is implicated as a key target for this sustained antidiabetic response 5 . While recent work points to a role for glia-neuron interactions leading to increased melanocortin signaling 7 , as well as to FGF1-induced changes in MBH extracellular matrix 8 , the signal transduction mechanisms by which FGF1 action in the MBH induces sustained remission of diabetic hyperglycemia is unknown.…”