New Insights of SF1 Neurons in Hypothalamic Regulation of Obesity and Diabetes

Abstract

Despite the substantial role played by the hypothalamus in the regulation of energy balance and glucose homeostasis, the exact mechanisms and neuronal circuits underlying this regulation remain poorly understood. In the last 15 years, investigations using transgenic models, optogenetic, and chemogenetic approaches have revealed that SF1 neurons in the ventromedial hypothalamus are a specific lead in the brain's ability to sense glucose levels and conduct insulin and leptin signaling in energy expenditure and glucose homeostasis, with minor feeding control. Deletion of hormonal receptors, nutritional sensors, or synaptic receptors in SF1 neurons triggers metabolic alterations mostly appreciated under high-fat feeding, indicating that SF1 neurons are particularly important for metabolic adaptation in the early stages of obesity. Although these studies have provided exciting insight into the implications of hypothalamic SF1 neurons on whole-body energy homeostasis, new questions have arisen from these results. Particularly, the existence of neuronal sub-populations of SF1 neurons and the intricate neurocircuitry linking these neurons with other nuclei and with the periphery. In this review, we address the most relevant studies carried out in SF1 neurons to date, to provide a global view of the central role played by these neurons in the pathogenesis of obesity and diabetes.

Keywords: SF1 neurons; diabetes; energy homeostasis; glucose homeostasis; obesity; ventromedial hypothalamus nucleus.

Figure 1

Schematic illustration of the pattern of genes highly expressed in the VMH. The majority of VMH cells, especially in the dorsomedial and central regions of VMH, express the nuclear receptor steroidogenic factor 1 (SF1). Leptin receptor (LEPR) positive cells mainly converge in the dorsomedial part, whereas insulin receptor (IR) maps the central region. Cells expressing brain-derived neurotrophic factor (BDNF) are mainly distributed in central and lateral areas of the VMH, estrogen receptor (ERα)-expressing cells are limited to the lateral region, and glucokinase (GK)-positive cells are present throughout the VMH. This schematic diagram is based on previous articles from Choi et al. [8] and Yi et al. [6].

Figure 2

Leptin and insulin signaling in SF1 neurons. Leptin binds LEPR to regulate body weight gain, energy expenditure, and insulin sensitivity in the VMH via STAT3 phosphorylation which is translocated into the nucleus and induces the expression of genes such as SOCS3, a negative regulator of LEPR. Leptin also stimulates a PI3K-dependent pathway, particularly involving subunits p110α, which contributes to energy expenditure regulation, and p110β, which contributes to both brown fat thermogenesis and glucose metabolism regulation in SF1 neurons. The Gsα subunit of G protein-coupled receptors (GPCR) of hormones and the protein-tyrosine phosphatase 1B (PTP1B) negatively regulates leptin action. The activation of this leptin signaling pathway triggers protection against obesity and diabetes under a high-fat diet (HFD) feeding. According to insulin signaling in SF1 neurons, exposure to HFD drives hyperinsulinemia, insulin binds insulin receptor (IR), which in turn activates PI3K that indirectly phosphorylates FOXO1 to induce transcription factors and promote obesity and glucose metabolism disruption.

Figure 3

Nutrient sensors in SF1 neurons regulate energy homeostasis. AMPK and SIRT1 are key nutrient sensors that restore energy balance under low energy availability. The role of both AMPK and SIRT1 in the central regulation of energy balance depends on their specific location in hypothalamic nuclei. AMPK in SF1 neurons of the VMH particularly regulates energy expenditure by acting in BAT thermogenesis and subcutaneous WAT browning (via sympathetic output) and liver lipogenesis (via parasympathetic output), whereas AMPK effects in feeding control and glucose balance mostly rely on ARC neurons. SIRT1 in SF1 VMH neurons controls insulin sensitivity in skeletal muscle protecting against diet-induced obesity, but in POMC neurons of the ARC, SIRT1 regulates normal BAT-like remodeling in specific fat depots. SIRT1 in SF1 neurons also contributes to the synchronization of the circadian clock in the brain by nutritional inputs. The arrow means increase and + means activation.

Figure 4

Glutamatergic neurotransmission and synaptic receptors in SF1 neurons and energy balance. Lack of the glutamate vesicular transporter VGLUT2 in SF1 neurons disrupts the glutamate effect in the postsynaptic receptors, leading to glucose metabolism dysfunction and a defective counterregulatory response (CRR). In line with this, the glutamate receptor mGluR5 in SF1 neurons also regulates glucose balance. The calcium channel subunit α2δ-1 is essential for excitability and firing activity of SF1 neurons which in turn regulate glucose metabolism in adipose tissue and skeletal muscle and lipolysis in white adipose tissue with no alterations in food intake. Finally, the endocannabinoid 2-arachidonoylglycerol (2-AG) released in the post-synaptic neuron, leads to retrograde activation of the CB1 receptor located in the presynaptic glutamatergic SF1 neurons, blocking calcium entry with subsequent inhibition of glutamatergic output and attenuation of POMC neurons activation, promoting food intake in diet-induced obesity.

Figure 5

Neurocircuitry linking SF1 VMH neurons to other brain areas in energy balance. Using optogenetic tools, the paraventricular nucleus of the hypothalamus (PVN) has been identified as a downstream target nucleus underlying the SF1 suppression of food intake. Downstream projections of SF1 in the VMH involved in the control of glycemia are the bed nucleus of the stria terminalis (aBNST) since photostimulation of the VMH^Sf1-aBNST circuit leads to increases in blood glucose levels. Finally, SF1 neurons are innervated by upstream BNST neurons and send projection to the nucleus tractus solitarius (NST) to regulate anxiety-like behavior and bone metabolism.