A Serotonin-Dependent Mechanism Explains the Leptin Regulation of Bone Mass, Appetite, and Energy Expenditure

Yadav, Vijay K.; Oury, Franck; Suda, Nina; Liu, Zhongwu; Gao, Xiao‐Bing; Confavreux, Cyrille; Klemenhagen, Kristen C.; Tanaka, Kenji F.; Gingrich, Jay A.; Guo, X. Edward; Tecott, Laurence H.; Mann, J. John; Hen, René; Horváth, Tamas L.; Karsenty, Gérard

doi:10.1016/j.cell.2009.06.051

Cited by 577 publications

(613 citation statements)

References 48 publications

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“…These latter findings correspond to the aforementioned effects on food intake, confirming that the impact of 5-HT1A receptor activation on food intake depends on the nutritional status [132,138]. A knockout of this receptor leads to reduced food intake [41]. Very likely, the knockout will diminish or eliminate the negative somatodendritic feedback and thus increase 5-HT release that will induce hypophagia via postsynaptic 5-HT2C and 5-HT1B receptor activation, although no change in habitual feeding in 5-HT1A receptor knockout mice has been displayed in another study [139].…”

supporting

confidence: 81%

“…The lack of brain 5-HT in conjunction with reduced food intake in Tph2 knockout mice seems to be at odds with the concept of 5-HT as satiety factor in the brain, but as this is a constitutional knockout, further research into developmental and aberrations and compensatory effects is required. The upregulation of uncoupling protein 1 (Ucp1) and increased catecholamine levels [41] in Tph2 knockout mice suggest that metabolic effects including a stimulated thermogenesis contribute to the phenotype. In contrast to these genetic studies, irreversible pharmacological inhibition of tryptophan hydroxylase by pchlorophenylalanine (pCPA) followed by depletion of brain 5-HT, increases food intake [43].…”

Section: Brain 5-ht and Satietymentioning

confidence: 99%

“…A Tph2 knockout in mice leads to retarded growth and lower body weight in early postnatal development [39,40]. An independent study found decreased food intake and bone mass in these mice [41] and the effects on body weight could possibly be gender dependent [42]. The lack of brain 5-HT in conjunction with reduced food intake in Tph2 knockout mice seems to be at odds with the concept of 5-HT as satiety factor in the brain, but as this is a constitutional knockout, further research into developmental and aberrations and compensatory effects is required.…”

mentioning

confidence: 99%

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Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

257

167

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Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 IntroductionWhat are the behavioural and physiological mechanisms that promote satiety? How is satiety defined? Satiety can be seen as a behavioural state which arises from food consumption and suppresses the initiation of eating for a particular period of time [1]. This description alone suggests a high degree of complexity as peripheral post-ingestive and post-absorptive signals need to be relayed to the brain where they are integrated with other signals to produce (or not) the behavioural state called satiety. The state of satiety is brought about a process called satiation, where sensory, cognitive and early post-ingestive mechanisms bring feeding to a halt and thus stopping a meal. Promoting satiation alone must not necessarily lead to reduced total food intake as the frequency of meals could be increased subsequently. Many peripheral and brain mechanisms have been identified that are involved in the expression satiety and it has been suggested that serotonin accelerates satiation and prolongs satiety [2]. In the following, we will review the role of serotonin in satiety in more detail 1 . The reader will see that, despite immense progress made during the last years, the field is still far from being resolved.As serotonin (5-Hydroxytryptamine; 5-HT) is a phylogenetically old neurotransmitter, various functions had time to evolve in different phyla, but maybe also in different species. 5-HT receptors exist in animal cells for millions of years and they are as old as adrenoreceptors ore some peptide receptors, possibly even older [5,6]. Even in invertebrates such as molluscs (Aplysia californica) and annelids (Hirudo medicinalis), 5-HT might functionally be related to food intake [7]. 5-HT is involved in feeding even in the honeybee where it has separate effects in the gut and in the insect brain [8]. In general, however, 5-HT seems rather to be involved in appetitive behaviours in invertebrates whereas it has more of a satiating effect in vertebrates [9]. In general, 5-HT neurons seem to be more extensively distributed throughout the body in lower animals than in higher animals including mammals where 5-HT neurones...

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supporting

confidence: 81%

Section: Brain 5-ht and Satietymentioning

confidence: 99%

mentioning

confidence: 99%

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Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

257

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“…The concept of control of bone mass and remodeling by the gastro-intestinal tract has emerged in the last decade. Recently, a role for gut-derived serotonin in the control of bone remodeling has been evidenced [30,31] as well as a link between glucagon-like peptide-2 and bone resorption [2]. In the present study, the role of GIP, a gut peptide, in controlling bone mass and microarchitecture was investigated.…”

Section: Discussionmentioning

confidence: 88%

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice

Gaudin-Audrain¹,

Irwin²,

Mansur³

et al. 2013

Bone

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A role for the gastro-intestinal tract in controlling bone remodeling is suspected since serum levels of bone remodeling markers are affected rapidly after a meal. Glucose-dependent insulinotropic polypeptide (GIP) represents a suitable candidate in mediating this effect. The aim of the present study was to investigate the effect of total inhibition of GIP signaling on trabecular bone volume, microarchitecture and quality. We used GIP receptor (GIPR) knockout mice and investigated trabecular bone volume and microarchitecture by microCT and histomorphometry. GIPR-deficient animals at 16 weeks of age presented with a significant (20%) increase in trabecular bone mass accompanied by an increase (17%) in trabecular number. In addition, the number of osteoclasts and bone formation rate was significantly reduced and augmented, respectively in these animals when compared with wild-type littermates. These modifications of trabecular bone microarchitecture are linked to a remodeling in the expression pattern of adipokines in the GIPR-deficient mice. On the other hand, despite significant enhancement in bone volume, intrinsic mechanical properties of the bone matrix was reduced as well as the distribution of bone mineral density and the ratio of mature/immature collagen cross-links. Taken together, these results indicate an increase in trabecular bone volume in GIPR KO animals associated with a reduction in bone quality.

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“…This discovery process started a decade ago with demonstration of a link among energy metabolism, the brain, and bone mass-a field that is now moving in two distinct but complementary directions: One line of inquiry continues to explore how leptin, serotonin, and other molecules orchestrate the central control of bone mass, (1,2) and the other focuses on bone as an endocrine organ critical for global regulation of energy metabolism and is the topic of this perspective. The fact that energy metabolism affects bone mass accrual by acting through a neuronal relay on one cell type, the osteoblast, raised the testable hypothesis that, in turn, the osteoblast might secrete one or several hormones affecting energy metabolism.…”

Section: Introductionmentioning

confidence: 99%

The osteoblast: An insulin target cell controlling glucose homeostasis

Clemens

Karsenty

2010

Journal of Bone and Mineral Research

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243

179

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The past five years have witnessed the emergence and discovery of unexpected functions played by the skeleton in whole-organism physiology. Among these newly described tasks is the role of bone in the control of energy metabolism, which is achieved through the secretion of osteocalcin, an osteoblasts-derived hormone regulating insulin secretion, insulin sensitivity, and energy expenditure. These initial findings raised several fundamental questions on the nature of insulin action in bone. Discoveries made independently by our two groups have provided answers recently to some of these questions. Through the analysis of mice lacking insulin receptor (InsR) only in osteoblasts, we found that insulin signaling in these cells favors whole-body glucose homeostasis. Importantly, this function of insulin signaling in osteoblasts was achieved through the negative regulation of osteocalcin carboxylation and bioavailability. Our studies also established that insulin signaling in osteoblasts was a positive regulator not only of postnatal bone acquisition but also of bone resorption. Interestingly, it appears that insulin signaling in osteoblasts induced osteocalcin activation by stimulating osteoclast activity. Indeed, the low pH generated during bone resorption is a sufficient means to decarboxylate osteocalcin. Our findings establish that the osteoblast is an important target used by insulin to control whole-body glucose homeostasis and identify bone resorption as the mechanism regulating osteocalcin activation. ß

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A Serotonin-Dependent Mechanism Explains the Leptin Regulation of Bone Mass, Appetite, and Energy Expenditure

Cited by 577 publications

References 48 publications

Serotonin controlling feeding and satiety

Serotonin controlling feeding and satiety

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice

The osteoblast: An insulin target cell controlling glucose homeostasis

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