Sweet Taste Receptor Serves to Activate Glucose- and Leptin-Responsive Neurons in the Hypothalamic Arcuate Nucleus and Participates in Glucose Responsiveness.

Daisuke Kohno,Miho Koike,Tadahiro Kitamura,Itaru Kojima,Yuzo Ninomiya,Toshihiko Yada

doi:10.3389/fnins.2016.00502

Abstract

The hypothalamic feeding center plays an important role in energy homeostasis. In the feeding center, whole-body energy signals including hormones and nutrients are sensed, processed, and integrated. As a result, food intake and energy expenditure are regulated. Two types of glucose-sensing neurons exist in the hypothalamic arcuate nucleus (ARC): glucose-excited neurons and glucose-inhibited neurons. While some molecules are known to be related to glucose sensing in the hypothalamus, the mechanisms underlying glucose sensing in the hypothalamus are not fully understood. The sweet taste receptor is a heterodimer of taste type 1 receptor 2 (T1R2) and taste type 1 receptor 3 (T1R3) and senses sweet tastes. T1R2 and T1R3 are distributed in multiple organs including the tongue, pancreas, adipose tissue, and hypothalamus. However, the role of sweet taste receptors in the ARC remains to be clarified. To examine the role of sweet taste receptors in the ARC, cytosolic Ca2+ concentration ([Ca2+]i) in isolated single ARC neurons were measured using Fura-2 fluorescent imaging. An artificial sweetener, sucralose at 10−5–10−2 M dose dependently increased [Ca2+]i in 12–16% of ARC neurons. The sucralose-induced [Ca2+]i increase was suppressed by a sweet taste receptor inhibitor, gurmarin. The sucralose-induced [Ca2+]i increase was inhibited under an extracellular Ca2+-free condition and in the presence of an L-type Ca2+ channel blocker, nitrendipine. Sucralose-responding neurons were activated by high-concentration of glucose. This response to glucose was markedly suppressed by gurmarin. More than half of sucralose-responding neurons were activated by leptin but not ghrelin. Percentages of proopiomelanocortin (POMC) neurons among sucralose-responding neurons and sweet taste receptor expressing neurons were low, suggesting that majority of sucralose-responding neurons are non-POMC neurons. These data suggest that sweet taste receptor-mediated cellular activation mainly occurs on non-POMC leptin-responding neurons and contributes to glucose responding. Endogenous sweet molecules including glucose may regulate energy homeostasis through sweet taste receptors on glucose-and leptin-responsive neurons in the ARC.

Highlights

The feeding center in the hypothalamus plays an important role in energy homeostasis
Peak fura-2 ratio amplitudes of response to sucralose at 10−5, 10−4, 10−3, and 10−2 M were significantly higher than the peak amplitude of basal fura-2 oscillation level (Figure 1C)
We found that an artificial sweetener, sucralose, at 10−5–10−2 M increases [Ca2+]i in ∼15% of arcuate nucleus (ARC) neurons through the sweet taste receptor-mediated pathway

Summary

Introduction

The feeding center in the hypothalamus plays an important role in energy homeostasis. Neurons in the feeding center are activated or suppressed by the molecules reflecting peripheral energy status, including hormones such as ghrelin, leptin and insulin, and nutrients such as glucose, free fatty acids, and amino acids. These neuronal responses are integrated by intracellular signaling and the brain circuit; as a result, feeding and metabolism are controlled (Williams and Elmquist, 2012). One is the glucose-excited (or glucose-responsive) neurons, which are activated by high concentrations of glucose and inhibited by low concentrations of glucose They are thought to be satiety neurons. The precise mechanisms underlying glucose-sensing in the hypothalamus are not fully understood

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Results

Conclusion