Near-Perfect Synaptic Integration by Nav1.7 in Hypothalamic Neurons Regulates Body Weight. 2016
Neurons are well suited for computations on millisecond timescales, but some neuronal circuits set behavioral states over long time periods, such as those involved in energy homeostasis. We found that multiple types of hypothalamic neurons, including those that oppositely regulate body weight, are specialized as near-perfect synaptic integrators that summate inputs over extended timescales. Excitatory postsynaptic potentials (EPSPs) are greatly prolonged, outlasting the neuronal membrane time-constant up to 10-fold. This is due to the voltage-gated sodium channel Nav1.7 (Scn9a), previously associated with pain-sensation but not synaptic integration. Scn9a deletion in AGRP, POMC, or paraventricular hypothalamic neurons reduced EPSP duration, synaptic integration, and altered body weight in mice. In vivo whole-cell recordings in the hypothalamus confirmed near-perfect synaptic integration. These experiments show that integration of synaptic inputs over time by Nav1.7 is critical for body weight regulation and reveal a mechanism for synaptic control of circuits regulating long term homeostatic functions.
Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss. 2015
Molecular and cellular processes in neurons are critical for sensing and responding to energy deficit states, such as during weight-loss. Agouti related protein (AGRP)-expressing neurons are a key hypothalamic population that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific transcriptomics can be used to identify pathways that counteract weight-loss, and here we report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived young adult mice. For comparison, we also analyzed Proopiomelanocortin (POMC)-expressing neurons, an intermingled population that suppresses appetite and body weight. We find that AGRP neurons are considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion channels, neuropeptides, and receptors. Combined with methods to validate and manipulate these pathways, this resource greatly expands molecular insight into neuronal regulation of body weight, and may be useful for devising therapeutic strategies for obesity and eating disorders.
Agouti related protein (AGRP)-expressing neurons are a key hypothalamic population that is activated during energy deficit and increases appetite and weight-gain.
Proopiomelanocortin (POMC)-expressing neurons, an intermingled population that suppresses appetite and body weight.
Effects of electroacupuncture Zusanli (ST36) on food intake and expression of POMC and TRPV1 through afferents-medulla pathway in obese prone rats. 2013
The purpose of this study was to determine the effects of electroacupuncture (EA) ST36 on food intake and body weight in obese prone (OP) rats compared to obese resistant (OR) strain on a high fat diet. The influences of EA on mRNA levels of pro-opiomelanocortin (POMC), transient receptor potential vanilloid type-1 (TRPV1), and neuronal nitric oxide synthase (nNOS) were also examined in the medulla regions and ST36 skin tissue.
Advanced EA ST36 was conducted in two sessions of 20 min separated by an 80 min interval for 7 days. Food intake and body weight were recorded in conscious rats every day. Real time PCR was conducted in the micropunches of the medulla regions and skin tissues at the end of the treatment.
Food intake and body weight were significantly reduced by advanced EA ST36 in OP rats, but slightly decreased in OR strain and sham-EA rats. Advanced EA ST36 produced a marked increase in POMC mRNA level in the nucleus tractus solitarius (NTS) and hypoglossal nucleus (HN) regions. TRPV1 and nNOS mRNAs were simultaneously increased in the NTS/gracile nucleus regions and in the ST36 skin regions by the EA treatment in OP rats.
We conclude that advanced EA ST36 produces an up-regulation of anorexigenic factor POMC production in the NTS/HN, which inhibits food intake and reduces body weight. EA-induced expression of TRPV1-nNOS in the ST36 and the NTS/gracile nucleus is involved in the signal transduction of EA stimuli via somatosensory afferents-medulla pathways.
ACTH inhibits the capsaicin-evoked release of CGRP from rat adrenal afferent nerves. 2001
The adrenal cortex is innervated by afferent fibers that have been implicated in affecting cortical steroidogenesis. Modulation of neurotransmitter release from afferents may represent a regulatory system for the control of adrenal cortical function. The present studies validate an in vitro superfusion technique for adrenal capsules employing the drug capsaicin, which activates a subset of afferent fibers and induces the release of calcitonin gene-related peptide (CGRP). Capsaicin-evoked CGRP release from adrenal afferents was blocked by capsazepine, a competitive antagonist for the capsaicin receptor, or by removal of extracellular calcium. Exogenous ACTH prevented capsaicin-evoked CGRP release, elevated basal aldosterone release, and prevented capsaicin-induced reduction in aldosterone release. Immunolabeling for the recently cloned capsaicin vanilloid receptor 1 demonstrated its presence in adrenal nerves. These results show that in vitro superfusion of adrenal capsules can be used to characterize factors that modulate neurotransmitter release from adrenal afferents. Furthermore, the results suggest that activation of adrenal afferents in vivo may attenuate aldosterone steroidogenesis and that high levels of ACTH may prevent this phenomenon.
The obesity-associated transcription factor ETV5 modulates circulating glucocorticoids. 2015
The transcription factor E-twenty-six version 5 (ETV5) has been linked with obesity in genome-wide association studies. Moreover, ETV5-deficient mice (knockout; KO) have reduced body weight, lower fat mass, and are resistant to diet-induced obesity, directly linking ETV5 to the regulation of energy balance and metabolism. ETV5 is expressed in hypothalamic brain regions that regulate both metabolism and HPA axis activity, suggesting that ETV5 may also modulate HPA axis function. In order to test this possibility, plasma corticosterone levels were measured in ETV5 KO and wildtype (WT) mice before (pre-stress) and after (post-stress) a mild stressor (intraperitoneal injection). ETV5 deficiency increased both pre- and post-stress plasma corticosterone, suggesting that loss of ETV5 elevated glucocorticoid tone. Consistent with this idea, ETV5 KO mice have reduced thymus weight, suggestive of increased glucocorticoid-induced thymic involution. ETV5 deficiency also decreased the mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and vasopressin receptor 1A in the hypothalamus, without altering vasopressin, corticotropin-releasing hormone, or oxytocin mRNA expression. In order to test whether reduced MR and GR expression affected glucocorticoid negative feedback, a dexamethasone suppression test was performed. Dexamethasone reduced plasma corticosterone in both ETV5 KO and WT mice, suggesting that glucocorticoid negative feedback was unaltered by ETV5 deficiency. In summary, these data suggest that the obesity-associated transcription factor ETV5 normally acts to diminish circulating glucocorticoids. This might occur directly via ETV5 actions on HPA-regulatory brain circuitry, and/or indirectly via ETV5-induced alterations in metabolic factors that then influence the HPA axis.
POMC = COLI_HUMAN
- (AGRP)-expressing neurons are a key hypothalamic population that is activated during energy deficit and increases appetite and weight-gain.
- Proopiomelanocortin (POMC)-expressing neurons, an intermingled population that suppresses appetite and body weight.