AgRP Neurons Regulate Bone Mass

Kim, Jae Geun; Sun, Ben‐hua; Dietrich, Marcelo O.; Koch, Marco; Yao, Gang‐Qing; Diano, Sabrina; Insogna, Karl L.; Horváth, Tamas L.

doi:10.1016/j.celrep.2015.08.070

Cited by 42 publications

(55 citation statements)

References 26 publications

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“…It is likely that leptin acts on galanin-expressing neurons, other than AgRP or POMC, because leptin receptor deletion from these neurons, previously shown to increase body weight and adiposity, (68) did not affect bone. (69) Interestingly, although the bone-accrual response to AP1 antagonism is enhanced in the absence of leptin, the femoral % BV/TV of ob/ob mice is lower at 15 weeks of age ( Fig. 3A) and unchanged at 40 weeks of age ( Fig.…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 90%

ΔFosB Requires Galanin, but not Leptin, to Increase Bone Mass via the Hypothalamus, but both are needed to increase Energy expenditure

Idelevich

Sato

Nagano

et al. 2019

Journal of Bone and Mineral Research

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Energy metabolism and bone homeostasis share several regulatory pathways. The AP1 transcription factor ΔFosB and leptin both regulate energy metabolism and bone, yet whether their pathways intersect is not known. Transgenic mice overexpressing ΔFosB under the control of the Enolase 2 (ENO2) promoter exhibit high bone mass, high energy expenditure, low fat mass, and low circulating leptin levels. Because leptin is a regulator of bone and ΔFosB acts on leptin‐responsive ventral hypothalamic (VHT) neurons to induce bone anabolism, we hypothesized that regulation of leptin may contribute to the central actions of ΔFosB in the VHT. To address this question, we used adeno‐associated virus (AAV) expression of ΔFosB in the VHT of leptin‐deficient ob/ob mice and genetic crossing of ENO2‐ΔFosB with ob/ob mice. In both models, leptin deficiency prevented ΔFosB‐triggered reduction in body weight, increase in energy expenditure, increase in glucose utilization, and reduction in pancreatic islet size. In contrast, leptin deficiency failed to prevent ΔFosB‐triggered increase in bone mass. Unlike leptin deficiency, galanin deficiency blocked both the metabolic and the bone ΔFosB‐induced effects. Overall, our data demonstrate that, while the catabolic energy metabolism effects of ΔFosB require intact leptin and galanin signaling, the bone mass–accruing effects of ΔFosB require galanin but are independent of leptin. © 2019 American Society for Bone and Mineral Research.

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Section: Journal Of Bone and Mineral Researchmentioning

confidence: 90%

ΔFosB Requires Galanin, but not Leptin, to Increase Bone Mass via the Hypothalamus, but both are needed to increase Energy expenditure

Idelevich

Sato

Nagano

et al. 2019

Journal of Bone and Mineral Research

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“…Leptin inhibits bone formation through the sympathetic nervous system (14) and orexin is a critical regulator of skeletal homeostasis and exerts dual regulation of bone mass (16). Specific neuronal subtypes and circuits can also exert influence on the regulation of bone mass (32), such as AGRP neurons in the arcuate nucleus that regulate bone mass through the sympathetic nervous system (33). While genetic knocking down of CamKKβ and CamKIV in SF1 neurons in the VMH leads to severe low-bone mass (21), serotonin neurons in the raphe nucleus send axonal projections to VMH SF1 neurons and promote bone mass through Htr2c receptors on the SF1 neurons (15).…”

Section: Anxiety-related Disorders Central Molecules and Neural Circmentioning

confidence: 99%

Identification of a Central Neural Circuit that Regulates Anxiety-induced Bone Loss

Yang

Liu

Chen

et al. 2019

Preprint

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# These authors contributed equally to this work. One Sentence Summary: Identification of a new GABAergic neural circuit from forebrain to hypothalamus used for regulation of anxiety-induced bone loss. Abstract:The homeostasis of bone metabolism is finely regulated by the central nervous system and recent studies have suggested that mood disorders, such as anxiety, are closely related to bone metabolic abnormalities; however, our understanding of central neural circuits regulating bone metabolism is still largely limited. In this study, we first demonstrate that confined isolation of human participants under normal gravity resulted in decreased bone density and elevated anxiety levels. We then used an established mouse model to dissect the neural circuitry regulating anxiety-induced bone loss. Combining electrophysiological, optogenetic and chemogenetic approaches, we demonstrate that GABAergic neural circuitry in ventromedial hypothalamus (VMH) modulates anxiety-induced bone loss; importantly, the GABAergic input in VMHdm arose from a specific group of somatostatin neurons in the bed nucleus of the stria terminalis (BNST), which is both indispensable for anxiety-induced bone loss and able to trigger bone loss in the absence of stressors. VGLUT2 neurons in Nucleus tractus solitaries (NTS) and peripheral sympathetic system were employed by this BNST-VMH neural circuit to regulate anxiety-induced bone loss. Overall, we uncovered new GABAergic neural circuitry from the forebrain to hypothalamus, used in the regulation of anxiety-induced bone loss, and revealed a population of somatostatin neurons in BNST not previously implicated in bone mass regulation.These findings thus identify the underlying central neural mechanism of psychiatric disorders, such as anxiety, that influences bone metabolism at the circuit level.

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“…Although, NPY and AgRP neuropeptides are co‐expressed, AgRP neurons were recently shown to act as positive regulators of bone. Suppression of AgRP neuronal firing or targeted AgRP neuron destruction, produced an osteopenic phenotype, in part via the sympathetic nervous system (SNS) . Intuitively, the anti‐bone‐forming and pro‐bone‐forming effects of NPY and AgRP, respectively, might appear discrepant.…”

Section: Introductionmentioning

confidence: 99%

“…Global deletion of either AgRP or NPY neuropeptides has negligible effects on feeding and weight, whereas full ablation of AgRP or NPY neurons leads to starvation, indicating that neuron activity, rather than neuropeptide expression, is important for feeding regulation. Although the study linking AgRP and bone measured neuronal firing, most studies linking NPY and bone manipulated only the level of the neuropeptide …”

Section: Introductionmentioning

confidence: 99%

Both NPY-Expressing and CART-Expressing Neurons Increase Energy Expenditure and Trabecular Bone Mass in Response to AP1 Antagonism, But Have Opposite Effects on Bone Resorption

Idelevich

Sato

Avihai

et al. 2020

Journal of Bone and Mineral Research

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Energy metabolism and bone homeostasis share several neuronal regulatory pathways. Within the ventral hypothalamus (VHT), the orexigenic neurons co‐express Agouti‐related peptide (AgRP) and neuropeptide Y (NPY) and the anorexigenic neurons co‐express, α‐melanocyte stimulating hormone derived from proopiomelanocortin (POMC), and cocaine and amphetamine‐regulated transcript (CART). These neurons regulate both processes, yet their relative contribution is unknown. Previously, using genetically targeted activator protein (AP1) alterations as a tool, we showed in adult mice that AgRP or POMC neurons are capable of inducing whole‐body energy catabolism and bone accrual, with different effects on bone resorption. Here, we investigated whether co‐residing neurons exert similar regulatory effects. We show that AP1 antagonists targeted to NPY‐producing or CART‐producing neurons in adult mice stimulate energy expenditure, reduce body weight gain and adiposity and promote trabecular bone formation and mass, yet again via different effects on bone resorption, as measured by serum level of carboxy‐terminal collagen type I crosslinks (CTX). In addition, AP1 antagonists promote neurite expansion, increasing neurite number, length, and surface area in primary hypothalamic neuronal cultures. Overall, our data demonstrate that the orexigenic NPY and anorexigenic CART neurons both have the capacity to stimulate energy burning state and increase bone mass. © 2020 American Society for Bone and Mineral Research.

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AgRP Neurons Regulate Bone Mass

Cited by 42 publications

References 26 publications

ΔFosB Requires Galanin, but not Leptin, to Increase Bone Mass via the Hypothalamus, but both are needed to increase Energy expenditure

ΔFosB Requires Galanin, but not Leptin, to Increase Bone Mass via the Hypothalamus, but both are needed to increase Energy expenditure

Identification of a Central Neural Circuit that Regulates Anxiety-induced Bone Loss

Both NPY-Expressing and CART-Expressing Neurons Increase Energy Expenditure and Trabecular Bone Mass in Response to AP1 Antagonism, But Have Opposite Effects on Bone Resorption

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