Hypothalamic TTF-1 orchestrates the sensitivity of leptin

Park, Byong Seo; Kang, Dasol; Kim, Kwang Kon; Jeong, Bora; Lee, Tae Hwan; Park, Jeong Woo; Kimura, Shioko; Yeh, Jung‐Yong; Roh, Gu Seob; Lee, Chang-Joong; Yang, Sungchil; Yang, Sunggu; Kim, Jae Geun; Lee, Byung Ju

doi:10.1016/j.molmet.2022.101636

Cited by 2 publications

(3 citation statements)

References 38 publications

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“…It has been well documented that the insensitivity of appetite-regulating hypothalamic neurons in response to the metabolic shifts were observed in the HFD-induced obesity models [ 25 ]. For instance, HFD-induced obesity models display sensitivity reduction of the hypothalamic neurocircuitry to the circulating leptin, thereby disrupting the homeostatic behaviors, including increased food intake and reduced energy expenditure [ 25 , 26 ]. Therefore, we assumed that the results showing different patterns between SD- and HFD-fed groups might be due to different responsiveness of the hypothalamic neurocircuitry to the reduced glucose availability triggered by dapagliflozin.…”

Section: Discussionmentioning

confidence: 99%

Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition

Lee,

Jung,

Park

et al. 2023

Diabetes Metab J

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Background: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are currently used to treat patients with diabetes. Previous studies have demonstrated that treatment with SGLT-2 inhibitors is accompanied by altered metabolic phenotypes. However, it has not been investigated whether the hypothalamic circuit participates in the development of the compensatory metabolic phenotypes triggered by the treatment with SGLT-2 inhibitors.Methods: Mice were fed a standard diet or high-fat diet and treated with dapagliflozin, an SGLT-2 inhibitor. Food intake and energy expenditure were observed using indirect calorimetry system. The activity of hypothalamic neurons in response to dapagliflozin treatment was evaluated by immunohistochemistry with c-Fos antibody. Quantitative real-time polymerase chain reaction was performed to determine gene expression patterns in the hypothalamus of dapagliflozin-treated mice.Results: Dapagliflozin-treated mice displayed enhanced food intake and reduced energy expenditure. Altered neuronal activities were observed in multiple hypothalamic nuclei in association with appetite regulation. Additionally, we found elevated immunosignals of agouti-related peptide neurons in the paraventricular nucleus of the hypothalamus.Conclusion: This study suggests the functional involvement of the hypothalamus in the development of the compensatory metabolic phenotypes induced by SGLT-2 inhibitor treatment.

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Section: Discussionmentioning

confidence: 99%

Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition

Lee,

Jung,

Park

et al. 2023

Diabetes Metab J

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“…TTF-1 has been widely implicated in the hypothalamic regulation of energy homeostasis [4,6,8,9,40]. TTF-1 acts as an appetite-driving transcription factor that is stimulated in response to a decrease in body energy levels.…”

Section: Discussionmentioning

confidence: 99%

“…Overnight fasting induces an increase in TTF-1 expression, subsequently stimulating the expression of orexigenic AgRP and inhibiting anorexigenic POMC genes. However, this fasting-induced modulation of AgRP and POMC gene expression is impeded when TTF-1 synthesis is inhibited by RNA interference [8,9]. These findings suggest that TTF-1 plays a crucial role in regulating appetite behavior by controlling the expression of target neuropeptides during conditions of low body energy [8].…”

Section: Introductionmentioning

confidence: 98%

Sirtuin1-Mediated Deacetylation of Hypothalamic TTF-1 Contributes to the Energy Deficiency Response

Kang

Yang

Kim

et al. 2023

IJMS

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TTF-1 stimulates appetite by regulating the expression of agouti-related peptide (AgRP) and proopiomelanocortin (POMC) genes in the hypothalamus of starving animals. However, the mechanism underlying TTF-1’s response to decreased energy levels remains elusive. Here, we provide evidence that the NAD+-dependent deacetylase, sirtuin1 (Sirt1), activates TTF-1 in response to energy deficiency. Energy deficiency leads to a twofold increase in the expression of both Sirt1 and TTF-1, leading to the deacetylation of TTF-1 through the interaction between the two proteins. The activation of Sirt1, induced by energy deficiency or resveratrol treatment, leads to a significant increase in the deacetylation of TTF-1 and promotes its nuclear translocation. Conversely, the inhibition of Sirt1 prevents these Sirt1 effects. Notably, a point mutation in a lysine residue of TTF-1 significantly disrupts its deacetylation and thus nearly completely hinders its ability to regulate AgRP and POMC gene expression. These findings highlight the importance of energy-deficiency-induced deacetylation of TTF-1 in the control of AgRP and POMC gene expression.

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Hypothalamic TTF-1 orchestrates the sensitivity of leptin

Cited by 2 publications

References 38 publications

Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition

Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition

Sirtuin1-Mediated Deacetylation of Hypothalamic TTF-1 Contributes to the Energy Deficiency Response

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