Identification of the leptin receptor sequences crucial for the STAT3-Independent control of metabolism

Barnes, Tammy M.; Shah, Kimi; Allison, Margaret B.; Steinl, Gabrielle K.; Gordian, Desiree; Sabatini, Paul V.; Tomlinson, Abigail J.; Cheng, Wenwen; Jones, Justin C.; Zhu, Qing; Faber, Chelsea L.; Myers, Martin G.

doi:10.1016/j.molmet.2019.12.013

Cited by 13 publications

(7 citation statements)

References 24 publications

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“… 67 The binding of leptin to its receptors leads to activation of Janus Kinase 2 (JAK2)/Signal Transducer And Activator Of Transcription 3 (STAT3), IRS-1, PI3K, and AMPK signaling pathways. 68 , 69 , 70 In particular, the activation of JAK2/STAT3 signaling was found to be critically involved in the modulatory effects of leptin on energy homeostasis. 70 When the cytosolic domain of the leptin receptor becomes phosphorylated by JAK proteins, it activates the MAPK/Extracellular Signal-Regulated Protein Kinase (ERK) 1/2 pathway.…”

Section: Introductionmentioning

confidence: 99%

Exercise training modulates adipokine dysregulations in metabolic syndrome

Babaei

Hoseini

2022

Sports Medicine and Health Science

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Section: Introductionmentioning

confidence: 99%

Exercise training modulates adipokine dysregulations in metabolic syndrome

Babaei

Hoseini

2022

Sports Medicine and Health Science

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“…For instance, the dose of leptin required to suppress food intake in rats is much higher than the dose required to produce maximal STAT3 activation (i.e., phospho-STAT3) within the ARC, suggesting that leptin-mediated activation of pSTAT3 is not sufficient to yield a full satiety-evoking effect (Harris, 2021). Moreover, mice lacking STAT3, or the tyrosine residue of LepR that recruits STAT3 (Tyr 1138 ), are less obese than mice lacking either leptin ( ob/ob ) or the leptin receptor ( db/db ), and leptin signaling remains partially intact in these mice (Barnes et al, 2020). These results suggest the existence of a STAT3-independent arm of LepR signaling.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest the existence of a STAT3-independent arm of LepR signaling. Interestingly, LepRb sequences between residues 921 and 960 have been implicated as indispensable for the STAT3-independent component of leptin’s metabolic actions (Barnes et al, 2020). Our data indicates a role for IRF3 as a transcriptional mediator of leptin action in AgRP neurons.…”

Section: Discussionmentioning

confidence: 99%

Integrated genomic analysis of AgRP neurons reveals that IRF3 regulates leptin’s hunger-suppressing effects

Heyward

Liu

Jacobs

et al. 2022

Preprint

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AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles during opposing states of fasting-induced hunger and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 28 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons, while live-cell imaging in vitro indicate that leptin can activate neuronal IRF3 in a cell autonomous manner. Finally, we employ CUT&RUN to uncover direct transcriptional targets of IRF3 in AgRP neurons in vivo. Thus, our findings identify AgRP neuron-expressed IRF3 as a key transcriptional effector of the hunger-suppressing effects of leptin.

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“…The above findings indicate the existence of some other yet-to-be-identified signal, independent of Tyr phosphorylation. LepRb regions that mediate such signals were recently identified by generating a series of mutant mice carrying LepRb truncation mutations [ 41 ]. LepRb sequences between residues 921 and 960, which contain no Tyr residues, mediated a signal involved in the control of feeding and energy balance.…”

Section: Leptin Receptor Signalingmentioning

confidence: 99%

Roles of Gangliosides in Hypothalamic Control of Energy Balance: New Insights

Inamori

Inokuchi

2020

IJMS

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Gangliosides are essential components of cell membranes and are involved in a variety of physiological processes, including cell growth, differentiation, and receptor-mediated signal transduction. They regulate functions of proteins in membrane microdomains, notably receptor tyrosine kinases such as insulin receptor (InsR) and epidermal growth factor receptor (EGFR), through lateral association. Studies during the past two decades using knockout (KO) or pharmacologically inhibited cells, or KO mouse models for glucosylceramide synthase (GCS; Ugcg), GM3 synthase (GM3S; St3gal5), and GD3 synthase (GD3S; St8sia1) have revealed essential roles of gangliosides in hypothalamic control of energy balance. The a-series gangliosides GM1 and GD1a interact with leptin receptor (LepR) and promote LepR signaling through activation of the JAK2/STAT3 pathway. Studies of GM3S KO cells have shown that the extracellular signal-regulated kinase (ERK) pathway, downstream of the LepR signaling pathway, is also modulated by gangliosides. Recent studies have revealed crosstalk between the LepR signaling pathway and other receptor signaling pathways (e.g., InsR and EGFR pathways). Gangliosides thus have the ability to modulate the effects of leptin by regulating functions of such receptors, and by direct interaction with LepR to control signaling.

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Identification of the leptin receptor sequences crucial for the STAT3-Independent control of metabolism

Cited by 13 publications

References 24 publications

Exercise training modulates adipokine dysregulations in metabolic syndrome

Exercise training modulates adipokine dysregulations in metabolic syndrome

Integrated genomic analysis of AgRP neurons reveals that IRF3 regulates leptin’s hunger-suppressing effects

Roles of Gangliosides in Hypothalamic Control of Energy Balance: New Insights

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