Revisiting the Ventral Medial Nucleus of the Hypothalamus: The Roles of SF-1 Neurons in Energy Homeostasis

Abstract

Obesity, diabetes, and other metabolic complications are growing concerns for public health and could lead to detrimental life-threatening conditions. Neurons whose activities are required for energy and glucose homeostasis are found in a number of hypothalamic nuclei. In the early twentieth century, the ventral medial nucleus of the hypothalamus (VMH) was the first site reported to play a prominent role in the regulation of energy homeostasis through control of food intake and energy expenditure. Recent studies using sophisticated genetic tools have further highlighted the importance of the VMH and have extended our understanding of the physiological role of the nucleus in regulation of energy homeostasis. These genetic studies were preceded by the identification of steroidogenic factor-1 (SF-1) as a marker of the VMH. This review focuses on the emerging homeostatic roles of the SF-1 neurons in the VMH discovered through the use of genetic models, particularly highlighting the control of energy, and glucose homeostasis.

Keywords: arcuate nucleus of the hypothalamus; energy homeostasis; glucose homeostasis; knockout; obesity; steroidogenic factor-1; ventral medial hypothalamic nucleus.

Figure 1

SF-1 neurons in the ventromedial hypothalamic nucleus (VMH). Figures show (A) the location of the hypothalamus in the CNS in a sagittal section and (B) the location of VMH in a coronal section. (C) (Upper) Nissle stained coronal section of the hypothalamus and (lower) schematic diagram of the hypothalamus within the coronal section. (D) Schematic diagram showing the pattern of genes expressed in the VMH. ARC, the arcuate nucleus. DMH, dorsomedial hypothalamic nucleus. LHA, lateral hypothalamic area. VMH, ventral medial nucleus of the hypothalamus. BDNF, brain-derived neurotrophic factor. ERα, estrogen receptor alpha. IR, insulin receptors. LepR, leptin receptors. SF-1, steroidogenic factor-1. Schematic diagrams were generated based on data from McClellan et al. (2006) and Yi et al. (2011).

Figure 2

Intracellular signaling in SF-1 neurons. Leptin binding to LEPRs induces auto-phosphorylation of LEPRs and phosphorylation of JAK2 (pJAK2), and subsequently these phosphorylated sites and pJAK2 induce phosphorylation of STAT3 (pSTAT3). pSTAT3 is translocated into the nucleus and alters the expression of several genes including SOCS3. SOCS3 negatively regulates JAK2 and other phosphorylated sites in LEPRs. Insulin binding to insulin receptors activates IRS and it activates PI3K. PI3K phosphorylates PIP2 and produces PIP3. PTEN dephosphorylates PIP3, thus generating PIP2. A recent study indicates PIP2 directly binds SF-1 in the nucleus (Blind et al., 2012). PIP3 phosphorylates AKT (pAKT) and pAKT induces phosphorylation of FOXO1 (pFOXO1) in the nucleus. pFOXO1 is translocated to the cytosol. FOXO1 directly binds SF-1 and inhibit SF-1 activity. AKT, serine/threonine-specific protein kinase. FOXO1, Forkhead box protein O1. JAK2, janus kinase 2. IRS, insulin receptor substrate. STAT3, signal transducer and activator of transcription. PIP2, phosphatidylinositol (4,5)-bisphosphate. PIP3, phosphatidylinositol (3,4,5)-triphosphate, PTEN, phosphatase and tensin homolog. P110, p110 catalytic subunit. P85, p85 regulatory subunit. SIRT1, sirtuin 1 or silent mating type information regulation 2. SF-1, steroidogenic factor-1. SOCS3, suppressor of cytokine signaling-3.