GABAergic RIP-Cre Neurons in the Arcuate Nucleus Selectively Regulate Energy Expenditure

Kong, Dong; Tong, Qingchun; Ye, Chianping; Koda, Shuichi; Fuller, Patrick M.; Krashes, Michael J.; Vong, Linh; Ray, Russell; Olson, David P.; Lowell, Bradford B.

doi:10.1016/j.cell.2012.09.020

Cited by 196 publications

(238 citation statements)

References 65 publications

(107 reference statements)

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“…By contrast, stimulation of the PVN by PACAP did not significantly alter these measures of energy expenditure despite evidence of PVN regulation of sympathetic outflow to BAT (3,46) and its control over the sympathetically driven PACAP-induced glycemic response (60). However, these results are in agreement with reports that PVN neurons inhibit sympathetic activity to BAT (33,37).…”

Section: Discussioncontrasting

confidence: 48%

Intrahypothalamic pituitary adenylate cyclase-activating polypeptide regulates energy balance via site-specific actions on feeding and metabolism

Resch

Maunze

Gerhardt

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Resch JM, Maunze B, Gerhardt AK, Magnuson SK, Phillips KA, Choi S. Intrahypothalamic pituitary adenylate cyclase-activating polypeptide regulates energy balance via site-specific actions on feeding and metabolism. Am J Physiol Endocrinol Metab 305: E1452-E1463, 2013. First published October 22, 2013; doi:10.1152/ajpendo.00293.2013.-Numerous studies have demonstrated that both the hypothalamic paraventricular nuclei (PVN) and ventromedial nuclei (VMN) regulate energy homeostasis through behavioral and metabolic mechanisms. Receptors for pituitary adenylate cyclase-activating polypeptide (PACAP) are abundantly expressed in these nuclei, suggesting PACAP may be critical for the regulation of feeding behavior and body weight. To characterize the unique behavioral and physiological responses attributed to select hypothalamic cell groups, PACAP was site-specifically injected into the PVN or VMN. Overall food intake was significantly reduced by PACAP at both sites; however, meal pattern analysis revealed that only injections into the PVN produced significant reductions in meal size, duration, and total time spent eating. PACAP-mediated hypophagia in both the PVN and VMN was abolished by PAC1R antagonism, whereas pretreatment with a VPACR antagonist had no effect. PACAP injections into the VMN produced unique changes in metabolic parameters, including significant increases in core body temperature and spontaneous locomotor activity that was PAC1R dependent whereas, PVN injections of PACAP had no effect. Finally, PACAP-containing afferents were identified using the neuronal tracer cholera toxin subunit B (CTB) injected unilaterally into the PVN or VMN. CTB signal from PVN injections was colocalized with PACAP mRNA in the medial anterior bed nucleus of the stria terminalis, VMN, and lateral parabrachial nucleus (LPB), whereas CTB signal from VMN injections was highly colocalized with PACAP mRNA in the medial amygdala and LPB. These brain regions are known to influence energy homeostasis perhaps, in part, through PACAP projections to the PVN and VMN.feeding; activity; temperature; hypothalamus; rat PITUITARY ADENYLATE CYCLASE-ACTIVATING polypeptide (PACAP) is a key regulator of several hypothalamic systems, including stress (1), osmoregulation (17), thermoregulation (21), and body weight (27). PACAP was first discovered to influence energy homeostasis through inhibition of feeding in mice following a single intracerebroventricular (icv) injection of the peptide (39). These results combined with reports of dietspecific alterations of PACAP mRNA expression in the hypothalamic ventromedial nuclei (VMN) suggest that PACAP is responsive to nutritional status and directly tied to metabolic systems linked to energy expenditure (27,40). In addition to reducing food intake, icv administration of PACAP modulates autonomic nerve activity (55) as well as hepatic glucose production (60). As a ligand, PACAP binds to three different G protein-coupled receptors, the PAC1 receptor (PAC1R), and the receptors originally discovered as targets...

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Section: Discussioncontrasting

confidence: 48%

Intrahypothalamic pituitary adenylate cyclase-activating polypeptide regulates energy balance via site-specific actions on feeding and metabolism

Resch

Maunze

Gerhardt

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…It is interesting to note that the vast majority of leptin's antiobesity effects are also mediated by leptin receptors in GABAergic neurons rather than glutamatergic neurons (23). Recently, it was shown that GABA release from hypothalamic Rip2-Cre neurons regulates energy balance by stimulating thermogenesis and EE without affecting food intake (34). The overall phenotype of RIIβ KO mice suggests that they might have enhanced GABA release from Rip2-Cre neurons in response to leptin.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

Zheng¹,

Yang²,

Sikorski³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Targeted disruption of RIIβ-protein kinase A (PKA) in mice leads to a lean phenotype, increased nocturnal locomotor activity, and activation of brown adipose tissue. Because RIIβ is abundantly expressed in both white and brown adipose tissue as well as the brain, the contribution of neuronal vs. peripheral PKA to these phenotypes was investigated. We used a Cre-Lox strategy to reexpress RIIβ in a tissue-specific manner in either adipocytes or neurons. Mice with adipocyte-specific RIIβ reexpression remained hyperactive and lean, but pan-neuronal RIIβ reexpression reversed both phenotypes. Selective RIIβ reexpression in all striatal medium spiny neurons with Darpp32-Cre corrected the hyperlocomotor phenotype, but the mice remained lean. Further analysis revealed that RIIβ reexpression in D2 dopamine receptor-expressing medium spiny neurons corrected the hyperlocomotor phenotype, which demonstrated that the lean phenotype in RIIβ-PKA-deficient mice does not develop because of increased locomotor activity. To identify the neurons responsible for the lean phenotype, we used specific Cre-driver mice to reexpress RIIβ in agouti-related peptide (AgRP)-, proopiomelanocortin (POMC)-, single-minded 1 (Sim1)-, or steroidogenic factor 1 (SF1)-expressing neurons in the hypothalamus, but observed no rescue of the lean phenotype. However, when RIIβ was reexpressed in multiple regions of the hypothalamus and striatum driven by Rip2-Cre, or specifically in GABAergic neurons driven by Vgat-ires-Cre, both the hyperactive and lean phenotypes were completely corrected. Bilateral injection of adeno-associated virus1 (AAV1)-Cre directly into the hypothalamus caused reexpression of RIIβ and partially reversed the lean phenotype. These data demonstrate that RIIβ-PKA deficiency in a subset of hypothalamic GABAergic neurons leads to the lean phenotype.mouse genetics | obesity | exercise | cAMP W e reported previously that mice lacking the protein kinase A (PKA) regulatory subunit RΙΙβ (RΙΙβ KO) exhibit a 50% reduction in white adipose tissue (WAT) and are resistant to dietinduced obesity (DIO) and diabetes (1, 2). These mice have an extended lifespan and show diminished age-related metabolic dysfunctions such as fatty liver and insulin resistance (3). Compared with their WT littermates, RIIβ KO mice have normal to slightly increased food intake, a twofold increase in nocturnal physical activity, and a basal metabolic rate (VO 2 consumption) that is higher than WT if calculated based on total body weight (4-6). RIIβ is highly expressed in the mouse CNS, brown adipose tissue (BAT), and WAT with limited expression elsewhere (1, 7-9). At the molecular level, RIIβ deficiency is accompanied by a compensatory increase in the PKA regulatory subunit RIα, which results in increased basal PKA activity and decreased total C subunit activity in brain, BAT, and WAT (1). These changes in PKA subunit composition may also alter PKA holoenzyme localization to specific signaling complexes because RIIβ has a much higher affinity for anchoring proteins (AKAPs)...

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“…Since most of the nNOS neurons in the preoptic region express the NMDA receptor (26), which is involved in the onset of puberty (49) and regulates nNOS activity (19,26,50,51), it is tempting to speculate that glutamatergic neurons of the PMv morphologically and functionally interact with nNOS neurons of the preoptic region to regulate the activity of GnRH neurons, thus synchronizing the effects of leptin in the 2 regions. Curiously, cre-mediated excision of the LepR in glutamatergic neurons results in no striking metabolic or reproductive phenotype (52,53), suggesting that leptin signaling through glutamate is not required for fertility. Yet, the reactivation of the LepR in mice otherwise null for the LepR within the PMv, which houses predominantly glutamatergic neurons, is sufficient to rescue fertility (25).…”

Section: Discussionmentioning

confidence: 99%

Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction

Bellefontaine¹,

Chachlaki²,

Parkash³

et al. 2014

J. Clin. Invest.

112

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The transition to puberty and adult fertility both require a minimum level of energy availability. The adipocyte-derived hormone leptin signals the long-term status of peripheral energy stores and serves as a key metabolic messenger to the neuroendocrine reproductive axis. Humans and mice lacking leptin or its receptor fail to complete puberty and are infertile. Restoration of leptin levels in these individuals promotes sexual maturation, which requires the pulsatile, coordinated delivery of gonadotropin-releasing hormone to the pituitary and the resulting surge of luteinizing hormone (LH); however, the neural circuits that control the leptin-mediated induction of the reproductive axis are not fully understood. Here, we found that leptin coordinated fertility by acting on neurons in the preoptic region of the hypothalamus and inducing the synthesis of the freely diffusible volume-based transmitter NO, through the activation of neuronal NO synthase (nNOS) in these neurons. The deletion of the gene encoding nNOS or its pharmacological inhibition in the preoptic region blunted the stimulatory action of exogenous leptin on LH secretion and prevented the restoration of fertility in leptin-deficient female mice by leptin treatment. Together, these data indicate that leptin plays a central role in regulating the hypothalamo-pituitary-gonadal axis in vivo through the activation of nNOS in neurons of the preoptic region.

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GABAergic RIP-Cre Neurons in the Arcuate Nucleus Selectively Regulate Energy Expenditure

Cited by 196 publications

References 65 publications

Intrahypothalamic pituitary adenylate cyclase-activating polypeptide regulates energy balance via site-specific actions on feeding and metabolism

Intrahypothalamic pituitary adenylate cyclase-activating polypeptide regulates energy balance via site-specific actions on feeding and metabolism

Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction

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