Synaptic plasticity and the role of astrocytes in central metabolic circuits.

Neural circuits in the brain, primarily in the hypothalamus, are paramount to the homeostatic control of feeding and energy utilization. They integrate hunger, satiety, and body adiposity cues from the periphery and mediate the appropriate behavioral and physiological responses to satisfy the energy demands of the animal. Notably, perturbations in central homeostatic circuits have been linked to the etiology of excessive feeding and obesity. Considering the ever-changing energy requirements of the animal and required adaptations, it is not surprising that brain-feeding circuits remain plastic in adulthood and are subject to changes in synaptic strength as a consequence of nutritional status. Indeed, synapse density, probability of presynaptic transmitter release, and postsynaptic responses in hypothalamic energy balance centers are tailored to behavioral and physiological responses required to sustain survival. Mounting evidence supports key roles of astrocytes facilitating some of this plasticity. Here we discuss these synaptic plasticity mechanisms and the emerging roles of astrocytes influencing energy and glucose balance control in health and disease. This article is categorized under: Cancer > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.

mGluR5 in Astrocytes in the Ventromedial Hypothalamus Regulates Pituitary Adenylate Cyclase-Activating Polypeptide Neurons and Glucose Homeostasis.

The ventromedial hypothalamus (VMH) is a functionally heterogeneous nucleus critical for systemic energy, glucose, and lipid balance. We showed previously that the metabotropic glutamate receptor 5 (mGluR5) plays essential roles regulating excitatory and inhibitory transmission in SF1+ neurons of the VMH and facilitating glucose and lipid homeostasis in female mice. Although mGluR5 is also highly expressed in VMH astrocytes in the mature brain, its role there influencing central metabolic circuits is unknown. In contrast to the glucose intolerance observed only in female mice lacking mGluR5 in VMH SF1 neurons, selective depletion of mGluR5 in VMH astrocytes enhanced glucose tolerance without affecting food intake or body weight in both adult female and male mice. The improved glucose tolerance was associated with elevated glucose-stimulated insulin release. Astrocytic mGluR5 male and female mutants also exhibited reduced adipocyte size and increased sympathetic tone in gonadal white adipose tissue. Diminished excitatory drive and synaptic inputs onto VMH Pituitary adenylate cyclase-activating polypeptide (PACAP+) neurons and reduced activity of these cells during acute hyperglycemia underlie the observed changes in glycemic control. These studies reveal an essential role of astrocytic mGluR5 in the VMH regulating the excitatory drive onto PACAP+ neurons and activity of these cells facilitating glucose homeostasis in male and female mice.SIGNIFICANCE STATEMENT Neuronal circuits within the VMH play chief roles in the regulation of whole-body metabolic homeostasis. It remains unclear how astrocytes influence neurotransmission in this region to facilitate energy and glucose balance control. Here, we explored the role of the metabotropic glutamate receptor, mGluR5, using a mouse model with selective depletion of mGluR5 from VMH astrocytes. We show that astrocytic mGluR5 critically regulates the excitatory drive and activity of PACAP-expressing neurons in the VMH to control glucose homeostasis in both female and male mice. Furthermore, mGluR5 in VMH astrocytes influences adipocyte size and sympathetic tone in white adipose tissue. These studies provide novel insight toward the importance of hypothalamic astrocytes participating in central circuits regulating peripheral metabolism.

Astrocytic BDNF signaling within the ventromedial hypothalamus regulates energy homeostasis.

Brain-derived neurotrophic factor (BDNF) is essential for maintaining energy and glucose balance within the central nervous system. Because the study of its metabolic actions has been limited to effects in neuronal cells, its role in other cell types within the brain remains poorly understood. Here we show that astrocytic BDNF signaling within the ventromedial hypothalamus (VMH) modulates neuronal activity in response to changes in energy status. This occurs via the truncated TrkB.T1 receptor. Accordingly, either fasting or central BDNF depletion enhances astrocytic synaptic glutamate clearance, thereby decreasing neuronal activity in mice. Notably, selective depletion of TrkB.T1 in VMH astrocytes blunts the effects of energy status on excitatory transmission, as well as on responses to leptin, glucose and lipids. These effects are driven by increased astrocytic invasion of excitatory synapses, enhanced glutamate reuptake and decreased neuronal activity. We thus identify BDNF/TrkB.T1 signaling in VMH astrocytes as an essential mechanism that participates in energy and glucose homeostasis.

Central adiponectin administration reveals new regulatory mechanisms of bone metabolism in mice.

Adiponectin (APN), the most abundant adipocyte-secreted adipokine, regulates energy homeostasis and exerts well-characterized insulin-sensitizing properties. The peripheral or central effects of APN regulating bone metabolism are beginning to be explored but are still not clearly understood. In the present study, we found that APN-knockout (APN-KO) mice fed a normal diet exhibited decreased trabecular structure and mineralization and increased bone marrow adiposity compared with wild-type (WT) mice. APN intracerebroventricular infusions decreased uncoupling protein 1 (UCP1) expression in brown adipose tissue, epinephrine and norepinephrine serum levels, and osteoclast numbers, whereas osteoblast osteogenic marker expression and trabecular bone mass increased in APN-KO and WT mice. In addition, centrally administered APN increased hypothalamic tryptophan hydroxylase 2 (TPH2), cocaine- and amphetamine-regulated transcript (CART), and 5-hydroxytryptamine (serotonin) receptor 2C (Htr2C) expressions but decreased hypothalamic cannabinoid receptor-1 expression. Treatment of immortalized mouse neurons with APN demonstrated that APN-mediated effects on TPH2, CART, and Htr2C expression levels were abolished by downregulating adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif (APPL)-1 expression. Pharmacological increase in sympathetic activity stimulated adipogenic differentiation of bone marrow stromal cells (BMSC) and reversed APN-induced expression of the lysine-specific demethylases involved in regulating their commitment to the osteoblastic lineage. In conclusion, we found that APN regulates bone metabolism via central and peripheral mechanisms to decrease sympathetic tone, inhibit osteoclastic differentiation, and promote osteoblastic commitment of BMSC.

Hypothalamic dysfunction of the thrombospondin receptor α2δ-1 underlies the overeating and obesity triggered by brain-derived neurotrophic factor deficiency.

Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are critical components of the neural circuitry controlling appetite and body weight. Diminished BDNF signaling in mice results in severe hyperphagia and obesity. In humans, BDNF haploinsufficiency and the functional Bdnf Val66Met polymorphism have been linked to elevated food intake and body weight. The mechanisms underlying this dysfunction are poorly defined. We demonstrate a chief role of α2δ-1, a calcium channel subunit and thrombospondin receptor, in triggering overeating in mice with central BDNF depletion. We show reduced α2δ-1 cell-surface expression in the BDNF mutant ventromedial hypothalamus (VMH), an energy balance-regulating center. This deficit contributes to the hyperphagia exhibited by BDNF mutant mice because selective inhibition of α2δ-1 by gabapentin infusion into wild-type VMH significantly increases feeding and body weight gain. Importantly, viral-mediated α2δ-1 rescue in BDNF mutant VMH significantly mitigates their hyperphagia, obesity, and liver steatosis and normalizes deficits in glucose homeostasis. Whole-cell recordings in BDNF mutant VMH neurons revealed normal calcium currents but reduced frequency of EPSCs. These results suggest calcium channel-independent effects of α2δ-1 on feeding and implicate α2δ-1-thrombospondin interactions known to facilitate excitatory synapse assembly. Our findings identify a central mechanism mediating the inhibitory effects of BDNF on feeding. They also demonstrate a novel and critical role for α2δ-1 in appetite control and suggest a mechanism underlying weight gain in humans treated with gabapentinoid drugs.

Weighing in the role of BDNF in the central control of eating behavior.

The prevalence of obesity and its associated medical complications, including type 2 diabetes and cardiovascular disease, continues to rise globally. Lifestyle changes in the last decades have greatly contributed to the current obesity trends. However, inheritable biological factors that disrupt the tightly regulated equilibrium between caloric intake and energy expenditure also appear to play a critical part. Mounting evidence obtained from human and rodent studies suggests that perturbed brain-derived neurotrophic factor (BDNF) signaling in appetite-regulating centers in the brain might be a culprit. Here, we review findings that inform the critical roles of BDNF and its receptor TrkB in energy balance and reward centers of the brain impacting feeding behavior and body weight.