Diet-Induced Growth Is Regulated via Acquired Leptin Resistance and Engages a Pomc-Somatostatin-Growth Hormone Circuit

Löhr, Heiko; Heß, Simon; Pereira, Mafalda Maria Robalo de Azevedo Aleixo; Reinoß, Philip; Leibold, Sandra; Schenkel, Christel; Wunderlich, Claudia M.; Kloppenburg, Peter; Hammerschmidt, Matthias

doi:10.1016/j.celrep.2018.04.018

Cited by 41 publications

(32 citation statements)

References 48 publications

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“…More recently, Riddle and colleagues reported that cavefish, Mexican tetra ( Astyanax mexicanus ) which carries a mutation in the insulin receptor lead to insulin resistance, and this phenotype is beneficial to weight gain for survival in nutrient-limited environment ( 44 ). Moreover, the occurrence of LR in zebrafish larvae promoted excessive caloric intake when food resources were plentiful, suggesting LR could be an ancient mechanism to promote somatic growth ( 45 ). In the present two different DIO Nile tilapia models, carbohydrate represents the main energy source in HCD while lipid is the main one in HFD.…”

Section: Discussionmentioning

confidence: 99%

Leptin Selectively Regulates Nutrients Metabolism in Nile Tilapia Fed on High Carbohydrate or High Fat Diet

Liu

Ning

et al. 2018

Front. Endocrinol.

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Leptin is known to inhibit appetite and promote energy metabolism in vertebrates. Leptin resistance (LR) commonly occurs in diet-induced obesity (DIO) in mammals. However, the roles of leptin in the energy homeostasis in DIO animals with LR remain unclear. Here we first verified the high expression of leptin in subcutaneous adipose tissue (SCAT) as in liver in Nile tilapia. Furthermore, we produced two types of DIO Nile tilapia by using a high-carbohydrate diet (HCD) or a high-fat diet (HFD), and confirmed the existence of LR in both models. Notably, we found that HCD-DIO fish retained leptin action in the activation of lipid metabolism and showed LR in glucose metabolism regulation, while this selective leptin action between lipid and glucose metabolism was reversed in HFD-DIO fish. Fasting the fish for 1 week completely recovered leptin actions in the regulation of lipid and glucose metabolism. Therefore, leptin may retain more of its activities in animals with LR than previously believed. Evolutionally, this selective regulation of leptin in nutrients metabolism could be an adaptive mechanism in animals to store surplus calories when different types of food are abundant.

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Section: Discussionmentioning

confidence: 99%

Leptin Selectively Regulates Nutrients Metabolism in Nile Tilapia Fed on High Carbohydrate or High Fat Diet

Liu

Ning

et al. 2018

Front. Endocrinol.

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“…R26-fl-rxΔ-ZsGreen mice have been previously described ( Löhr et al., 2018 ). Homozygous mice were mated with MCH-Cre tg/wt mice to generate ZsGreen MCH mice.…”

Section: Methodsmentioning

confidence: 99%

MCH Neurons Regulate Permeability of the Median Eminence Barrier

Jiang

Gallet

Klemm

et al. 2020

Neuron

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Summary Melanin-concentrating hormone (MCH)-expressing neurons are key regulators of energy and glucose homeostasis. Here, we demonstrate that they provide dense projections to the median eminence (ME) in close proximity to tanycytes and fenestrated vessels. Chemogenetic activation of MCH neurons as well as optogenetic stimulation of their projections in the ME enhance permeability of the ME by increasing fenestrated vascular loops and enhance leptin action in the arcuate nucleus of the hypothalamus (ARC). Unbiased phosphoRiboTrap-based assessment of cell activation upon chemogenetic MCH neuron activation reveals MCH-neuron-dependent regulation of endothelial cells. MCH neurons express the vascular endothelial growth factor A (VEGFA), and blocking VEGF-R signaling attenuates the leptin-sensitizing effect of MCH neuron activation. Our experiments reveal that MCH neurons directly regulate permeability of the ME barrier, linking the activity of energy state and sleep regulatory neurons to the regulation of hormone accessibility to the ARC.

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“…Overfeeding per se led to glucose intolerance in fish independent of genotype, and loss of leptin function in addition to overfeeding did not impair glucose tolerance further. One recent study found that overfeeding of zebrafish larvae leads to leptin resistance and reduced hypothalamic pomca levels, leading to activation of the melanocortin system, elevation of growth hormone levels, and enhanced somatic growth [48]. Together, these data point towards a fundamentally differential physiological role for leptin depending on nutrient availability.…”

Section: Discussionmentioning

confidence: 99%

Leptin regulates glucose homeostasis via the canonical WNT pathway

Kamstra

Rizwan

Horsfield

et al. 2021

Preprint

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Leptin is a body weight regulatory hormone, but it is arguably even more potent at regulating blood glucose levels. To further our understanding of the molecular mechanisms by which leptin controls glucose homeostasis, we have used transgenic zebrafish models and conditional deletion of beta catenin in the mediobasal hypothalamus of adult mice to show that Wnt signalling in the brain mediates glucoregulatory effects of leptin. In zebrafish, under normal feeding conditions, leptin regulates glucose homeostasis but not adipostasis. In times of nutrient excess, we found that leptin also regulates body weight and size in this species. Using a Wnt signalling reporter fish, we show that leptin directly activates the canonical Wnt pathway in vivo. Pharmacological inhibition of this pathway prevented the leptin-induced improvement in glucose tolerance. In adult mice, conditional deletion of the key Wnt effector molecule, β-catenin, in the mediobasal hypothalamus of male mice confirmed the essential role of the Wnt pathway in mediating leptin action and the neuroendocrine regulation of glucose homeostasis. Adult-onset β-catenin deletion in the mediobasal hypothalamus led to glucose intolerance, exacerbation of caloric intake and body weight gain under high fat diet, as well as resistance to exogenous leptin.

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Diet-Induced Growth Is Regulated via Acquired Leptin Resistance and Engages a Pomc-Somatostatin-Growth Hormone Circuit

Cited by 41 publications

References 48 publications

Leptin Selectively Regulates Nutrients Metabolism in Nile Tilapia Fed on High Carbohydrate or High Fat Diet

Leptin Selectively Regulates Nutrients Metabolism in Nile Tilapia Fed on High Carbohydrate or High Fat Diet

MCH Neurons Regulate Permeability of the Median Eminence Barrier

Leptin regulates glucose homeostasis via the canonical WNT pathway

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