Control of Food Intake and Energy Expenditure by Nos1 Neurons of the Paraventricular Hypothalamus

Sutton, Amy K.; Pei, Hongjuan; Burnett, Korri H.; Myers, Martin G.; Rhodes, Christopher J.; Olson, David P.

doi:10.1523/jneurosci.0226-14.2014

Cited by 123 publications

(137 citation statements)

References 33 publications

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“…Future studies should determine whether chronic intranasal administration of OT recapitulates the effects of chronic subcutaneous administration to stimulate energy expenditure in DIO nonhuman primates [26] and whether these effects translate to obese humans. Sutton and colleagues demonstrated that acute CNO-induced activation of PVN OT neurons in oxytocin-Ires-Cre mice increased Fos in thoracic sympathetic preganglionic neurons in the spinal cord [89]. OT also activated thoracic sympathetic preganglionic neurons in the cat [136] as well as the stellate ganglia in the dog [137].…”

Section: Effects Of Ot On Energy Expenditurementioning

confidence: 99%

“…Existing data indicate that OT plays a critical role in the control of energy homeostasis [26][27][28][30][31][32][34][35][36]56,62,[79][80][81][82][83][84][85][86][87][88][89]. For example, global deficiencies in either OT [90] or OTRs [91] are associated with adult-onset obesity in mice.…”

Section: Role Of Ot Signaling In Energy Balancementioning

confidence: 99%

“…Conflicting with previous pharmacological studies, however, is a report that incorporated the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) technology in which Cre recombinasedependent adeno-associated virus (AAV)-hM3Dq was administered bilaterally into the PVN of mice. These investigators administered clozapine-N-oxide (CNO) to activate PVN OT neurons in oxytocin-IresCre mice [89], but this intervention failed to result in decreased consumption of chow relative to vehicle treatment. These findings raise important questions as to whether a) CNO-elicited activation of PVN OT neurons results in an anorexigenic response when administered during the light cycle at a time that coincides with the diurnal rhythmicity of circulating [32] or cerebrospinal fluid levels of OT [111] and b) the response varies with respect to energy status (fasted vs. ad libitum fed), or diet (chow, high fat or high fat/high sucrose diet).…”

Section: Intact Response To Ot Despite Impaired Leptin Signalingmentioning

confidence: 99%

See 2 more Smart Citations

Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans

Blevins

Baskin

2015

Physiology & Behavior

128

100

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The fact that more than 78 million adults in the US are considered overweight or obese highlights the need to develop new, effective strategies to treat obesity and its associated complications, including type 2 diabetes, kidney disease and cardiovascular disease. While the neurohypophyseal peptide oxytocin (OT) is well recognized for its peripheral effects to stimulate uterine contraction during parturition and milk ejection during lactation, release of OT within the brain is implicated in prosocial behaviors and in the regulation of energy balance. Previous findings indicate that chronic administration of OT decreases food intake and weight gain or elicits weight loss in diet-induced obese (DIO) mice and rats. Furthermore, chronic systemic treatment with OT largely reproduces the effects of central administration to reduce weight gain in DIO and genetically obese rodents at doses that do not appear to result in tolerance. These findings have now been recently extended to more translational models of obesity showing that chronic subcutaneous or intranasal OT treatment is sufficient to elicit body weight loss in DIO nonhuman primates and pre-diabetic obese humans. This review assesses the potential use of OT as a therapeutic strategy for treatment of obesity in rodents, nonhuman primates, and humans, and identifies potential mechanisms that mediate this effect.

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Section: Effects Of Ot On Energy Expenditurementioning

confidence: 99%

Section: Role Of Ot Signaling In Energy Balancementioning

confidence: 99%

Section: Intact Response To Ot Despite Impaired Leptin Signalingmentioning

confidence: 99%

See 1 more Smart Citation

Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans

Blevins

Baskin

2015

Physiology & Behavior

128

100

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“…Interestingly, gabazine had opposite effects on body temperature in the PVN and DMH, as expected from experiments in rats (32,33), which also confirms the site selectivity of the injections. Collectively these data suggest that neither AgRP nor GABA in PVN are involved in the suppression of SSNA or HR following ArcN AgRP/NPY neuronal activation, likely because of rons in the spinal cord (25). Therefore, given the profound sympathoinhibitory effects of NPY in the PVN in both mice ( Figure 3) and rats (4, 7, 26), we next considered potential explanations for the failure of PVN BIBO3304 administered after i.p.…”

Section: Selective Activation or Inhibition Of Arcn Npy/agrp Neurons mentioning

confidence: 99%

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

Shi¹,

Madden²,

Brooks³

2017

Journal of Clinical Investigation

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Obesity increases sympathetic nerve activity (SNA) via activation of proopiomelanocortin neurons in the arcuate nucleus (ArcN), and this action requires simultaneous withdrawal of tonic neuropeptide Y (NPY) sympathoinhibition. However, the sites and neurocircuitry by which NPY decreases SNA are unclear. Here, using designer receptors exclusively activated by designer drugs (DREADDs) to selectively activate or inhibit ArcN NPY neurons expressing agouti-related peptide (AgRP) in mice, we have demonstrated that this neuronal population tonically suppresses splanchnic SNA (SSNA), arterial pressure, and heart rate via projections to the paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMH The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 8 6 9 jci.org Volume 127 Number 7 July 2017We next tested whether selective excitation or inhibition of ArcN NPY/AgRP neurons alters splanchnic SNA (SSNA), mean AP (MAP), or heart rate (HR) ( Figure 1). As shown in representative experiments ( Figure 1, A and B) and grouped data ( Figure 1C), in ArcN hM3Dq mice, i.p. CNO (0.3 mg/kg) promptly decreased SSNA, MAP, and HR, whereas i.p. saline had no effects. The suppression induced by CNO was sustained for at least 1 hour, and, in mice with longer recordings, up to 4 hours (data not shown). In rats, guinea pigs, and humans, CNO can have nonspecific effects due to its conversion to clozapine (17, 18). However, in WT mice receiving the Cre-dependent hM3Dq vector, neither i.p. saline nor CNO significantly altered these variables, suggesting that CNO was not exerting its effects independently of DREADD activation. A separate group of Agrp-IRES-Cre mice instead received AAV-hM4Di-mCherry in the ArcN (Figure 1, D-F). In these ArcN hM4Di mice, i.p. CNO (0.3 and 1 mg/kg) dose-dependently increased SSNA, MAP, and HR, although the responses developed both NPY-GFP and Cre in AgRP neurons. In agreement with an earlier study using a different approach (14), we found that while not all NPY-GFP neurons had visible hM3Dq-mCherry labeling, 100% of the hM3Dq-mCherry-marked neurons also expressed NPY-GFP (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/JCI92008DS1). WT mice never expressed the Cre-dependent DREADD. In a second set of experiments, 2 or more weeks after Agrp-IRES-Cre mice received hM3Dq bilaterally in the ArcN, CNO (0.3 mg/kg) or the saline vehicle was administered i.p., and food intake was monitored for the following 4 hours. As shown previously (14), i.p. CNO, but not saline, rapidly evoked food intake in ArcN hM3Dq mice (Supplemental Figure 1). Conversely, activation of inhibitory DREADDs in ArcN hM4Di mice at the beginning of the feeding period (lights out) inhibited food intake (Supplemental Figure 1). Therefore, we anatomically and functionally confirm that this approach selectively targets ArcN NPY/AgRP neurons. The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 8 7 0jci.org Volume 127 Number 7 July 2017neurons were also observ...

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“…Recent studies indicate that in addition to suppressing food intake, oxytocin may also reduce body weight in rodents and nonhuman primates by increasing energy expenditure (10,63,90,99,(102)(103)(104). Conversely, animals with either partial or complete loss in oxytocin signaling show decreased energy expenditure (18,45,93,99,104) and brown adipose tissue thermogenesis (18,45,93).…”

mentioning

confidence: 99%

Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization

Blevins

Thompson²,

Anekonda³

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

131

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-Based largely on a number of short-term administration studies, growing evidence suggests that central oxytocin is important in the regulation of energy balance. The goal of the current work is to determine whether long-term third ventricular (3V) infusion of oxytocin into the central nervous system (CNS) is effective for obesity prevention and/or treatment in rat models. We found that chronic 3V oxytocin infusion between 21 and 26 days by osmotic minipumps both reduced weight gain associated with the progression of high-fat diet (HFD)-induced obesity and elicited a sustained reduction of fat mass with no decrease of lean mass in rats with established diet-induced obesity. We further demonstrated that these chronic oxytocin effects result from 1) maintenance of energy expenditure at preintervention levels despite ongoing weight loss, 2) a reduction in respiratory quotient, consistent with increased fat oxidation, and 3) an enhanced satiety response to cholecystokinin-8 and associated decrease of meal size. These weightreducing effects persisted for approximately 10 days after termination of 3V oxytocin administration and occurred independently of whether sucrose was added to the HFD. We conclude that long-term 3V administration of oxytocin to rats can both prevent and treat dietinduced obesity. obesity; food intake; energy expenditure; oxytocin PUBLISHED DATA suggest that in addition to its well-recognized peripheral effects on uterine contraction during parturition and milk ejection during lactation (33), the nonapeptide oxytocin plays an important role in the regulation of energy homeostasis (23,53,59,103,104). Transgenic mice with deficient oxytocin (18) or oxytocin receptor (OTR) signaling (93) exhibit adult-onset obesity, and copy number variations associated with the OTR gene (OXTR) are linked with an early-onset obesity phenotype in humans (96). Furthermore, impaired oxytocin release within the hypothalamic paraventricular nucleus (PVN) is evident in dietinduced obese (DIO) mice (103), which could lead to defects in peripheral release of oxytocin, and potentially explain the decreased circulating levels in DIO mice (103, 104), genetically obese rodents (32, 73), as well as obese humans and individuals with Type 2 diabetes (74). Moreover, the pathogenesis of PraderWilli syndrome, a rare human genetic disorder characterized by hyperphagia and severe obesity, is linked to a reduced size and number of PVN oxytocin neurons (91). Importantly, both acute and chronic administration of oxytocin is sufficient to bypass impaired leptin signaling to reduce weight gain or body weight in both DIO (23,53,59,103,104) and genetically obese rodent models (1,42,47,54,59,73) as well as weight loss in DIO rhesus monkeys (10) and humans (105). While collectively these findings are indicative of an important physiological role for oxytocin in energy homeostasis, the mechanisms underlying this function have not been fully elucidated.The effects of central nervous system (CNS) administration of oxytocin to reduce body weight gai...

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Control of Food Intake and Energy Expenditure by Nos1 Neurons of the Paraventricular Hypothalamus

Abstract: The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of Sim1-expressing cell types that comprise a major autonomic output nucleus and play critical roles in the control of food intake and energy homeostasis.

Cited by 123 publications

References 33 publications

Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans

Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization

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