Ventromedial hypothalamus–specific Ptpn1 deletion exacerbates diet-induced obesity in female mice

Chiappini, Franck; Catalano, Karyn J.; Lee, Jennifer; Peroni, Odile D.; Lynch, Jacqueline E; Dhaneshwar, Abha S.; Wellenstein, Kerry; Sontheimer, Alexandra; Neel, Benjamin G.; Kahn, Barbara B.

doi:10.1172/jci68585

Cited by 36 publications

(39 citation statements)

References 64 publications

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“…Moreover, it has been reported that SF1 neurons project to autonomic centers modulating the SNS (Lindberg et al., 2013, Chiappini et al., 2014). Given that T3 selectively regulates hypothalamic AMPKα1 (but not AMPKα2) expression and activity (López et al., 2010), we generated an SF1 neuron-specific AMPKα1 mouse line (SF1-Cre AMPKα1 flox/flox ) by crossing floxed AMPKα1 mice (Nakada et al., 2010) and SF1-Cre mice, which express Cre recombinase under SF1 promoter, hence targeting subsets of neurons of the VMH (Dhillon et al., 2006).…”

Section: Resultsmentioning

confidence: 99%

Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance

et al. 2017

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SummaryThyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPKα1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.

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Section: Resultsmentioning

confidence: 99%

Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance

et al. 2017

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“…These studies demonstrate the importance of IR signaling in the ARC for the regulation of physiological processes. It should be noted that IR is present in other hypothalamic and extrahypothalamic nuclei (10 -13) that are implicated in the regulation of feeding (48,49), adiposity (50), and sympathetic nerve traffic (51). The contribution of these other brain sites to insulin regulation of energy homeostasis and sympathetic activity remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

The Role of Hypothalamic mTORC1 Signaling in Insulin Regulation of Food Intake, Body Weight, and Sympathetic Nerve Activity in Male Mice

2015

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Insulin action in the brain particularly the hypothalamus is critically involved in the regulation of several physiological processes, including energy homeostasis and sympathetic nerve activity, but the underlying mechanisms are poorly understood. The mechanistic target of rapamycin complex 1 (mTORC1) is implicated in the control of diverse cellular functions, including sensing nutrients and energy status. Here, we examined the role of hypothalamic mTORC1 in mediating the anorectic, weight-reducing, and sympathetic effects of central insulin action. In a mouse hypothalamic cell line (GT1-7), insulin treatment increased mTORC1 activity in a time-dependent manner. In addition, intracerebroventricular (ICV) administration of insulin to mice activated mTORC1 pathway in the hypothalamic arcuate nucleus, a key site of central action of insulin. Interestingly, inhibition of hypothalamic mTORC1 with rapamycin reversed the food intake- and body weight-lowering effects of ICV insulin. Rapamycin also abolished the ability of ICV insulin to cause lumbar sympathetic nerve activation. In GT1-7 cells, we found that insulin activation of mTORC1 pathway requires phosphatidylinositol 3-kinase (PI3K). Consistent with this, genetic disruption of PI3K in mice abolished insulin stimulation of hypothalamic mTORC1 signaling as well as the lumbar sympathetic nerve activation evoked by insulin. These results demonstrate the importance of mTORC1 pathway in the hypothalamus in mediating the action of insulin to regulate energy homeostasis and sympathetic nerve traffic. Our data also highlight the key role of PI3K as a link between insulin receptor and mTORC1 signaling in the hypothalamus.

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“…However, PTP1B's role may be cell type-dependent, since PTP1B deletion in SF-1 neurons in the ventromedial hypothalamus enhances insulin signaling to suppress energy expenditure and promote weight gain in female mice [66], whereas PTP1B deletion in POMC neurons in the ARC has no effect on insulin signaling and glucose homeostasis, but enhances leptin signaling [39]. Rather, in POMC neurons, TCPTP may be the principal phosphatase attenuating insulin signaling [39].…”

Section: Ptps and Insulin Signalingmentioning

confidence: 99%

Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling

Zhang

Dodd

Tiganis

2015

Trends in Pharmacological Sciences

158

118

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Ventromedial hypothalamus–specific Ptpn1 deletion exacerbates diet-induced obesity in female mice

Cited by 36 publications

References 64 publications

Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance

Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance

The Role of Hypothalamic mTORC1 Signaling in Insulin Regulation of Food Intake, Body Weight, and Sympathetic Nerve Activity in Male Mice

Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling

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