Coordinated Regulation of Hepatic Energy Stores by Leptin and Hypothalamic Agouti-Related Protein

Warne, James P.; Varonin, Jillian M.; Nielsen, Sofie Sylvest; Olofsson, Louise E.; Kaelin, Christopher B.; Chua, Streamson; Barsh, Gregory S.; Koliwad, Suneil K.; Xu, Allison

doi:10.1523/jneurosci.0830-13.2013

Cited by 9 publications

(9 citation statements)

References 84 publications

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“…In mice, deficient leptin signaling in the hypothalamus blunts the fasting lead suppression of hepatic sympathetic activity and elevation of hepatic triglyceride content and steatosis [10]. Furthermore, severe hepatic steatosis seen in congenital lipodystrophies can be treated with metreleptin [11,24].…”

Section: Discussionmentioning

confidence: 99%

“…In mice, fasting leads to suppression of hepatic sympathetic activity and elevated hepatic triglyceride content and steatosis. These effects are blunted in mice with deficient leptin signaling in the AGRP neurons in the hypothalamus [10]. In humans, congenital leptin deficiency is associated with severe hepatic steatosis, which can be treated with metreleptin [11].…”

Section: Introductionmentioning

confidence: 99%

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Circulating fetuin-A levels are not affected by short and long-term energy deprivation and/or by leptin administration

et al. 2014

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Objective Fetuin-A may mediate cross-talk between the liver and adipose tissue. We studied the physiologic regulation of fetuin-A and explored its potential regulation by leptin. Design and Methods Fetuin-A levels were measured in three interventional studies as well as in in vitro experiments. Study 1: 15 lean subjects received placebo or physiologic replacement-dose recombinant human leptin (metreleptin) following short term complete caloric deprivation to induce severe hypoleptinemia; Study 2: 7 women with relative leptin deficiency due to strenuous exercise or low weight received 3 months of metreleptin; Study 3: 17 women with relative leptin deficiency were randomized to receive metreleptin or placebo over 9 months. In study 4 human hepatoma Hep G2 cells were treated with leptin. Fetuin-A mRNA expression and secretion were measured. Results Complete caloric deprivation significantly decreased leptin but had no effect on fetuin-A levels. Normalizing leptin levels with metreleptin in hypoleptinemic subjects had no effect on circulating fetuin-A levels. Leptin treatment had no effect on fetuin-A mRNA expression and secretion in vitro. Conclusions Circulating fetuin-A levels are not affected by short and long-term energy deprivation. Furthermore, both in vivo and in vitro experiments confirm that fetuin-A is not regulated by leptin.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Circulating fetuin-A levels are not affected by short and long-term energy deprivation and/or by leptin administration

et al. 2014

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“…These effects were dependent on hypothalamic leptin signaling and were, surprisingly, caused by a stimulation of SNS outfl ow to the liver, as evidenced by an increase in hepatic noradrenalin content ( 41 ). In addition, a recent follow-up study showed that leptin administration in 36 h-fasted mice decreased hepatic TG content, lipogenic gene expression, and VLDL-TG production ( 42 ). These data, however, should be taken with caution, as 36 h fasting is probably a nonphysiological metabolic condition for mice.…”

Section: Anatomy Of Hypothalamic Sympathetic Outflowmentioning

confidence: 99%

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies

Geerling

Boon

Kooijman

et al. 2014

Journal of Lipid Research

107

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Dyslipidemia is one of the classical risk factors for cardiovascular diseases (CVD) besides hypertension, type 2 diabetes, and smoking ( 1 ). Dyslipidemia is defi ned as an elevation of plasma LDL-cholesterol (LDL-C), triglycerides (TG), or both, with or without a lowering of HDLcholesterol (HDL-C) ( 2 ). Whereas elevated LDL-C is a well-established major predictor of CVD and has been the primary target for lipid-lowering strategies, evidence suggests that an elevated TG level is an independent risk factor for CVD development as well ( 3, 4 ). Plasma TG levels are considered elevated when they exceed 150 mg/dl, which is observed in 31% of the adult US population ( 5 ). Although hypertriglyceridemia can be caused by rare monogenic disorders, it is mostly caused by a complex interaction between environmental factors and subtle variations in genes involved in lipoprotein metabolism ( 5 ). Current treatments for hypertriglyceridemia are aimed at either increasing TG clearance (e.g., fi brates) ( 6 ) or at decreasing lipolysis in WAT (e.g., niacin) ( 7 ). In addition, reduction of VLDL-TG production lowers plasma TG levels (e.g., exendin-4) ( 8 ).In recent years, the autonomic nervous system, which consists of a sympathetic and a parasympathetic branch, emerged as an important regulator of metabolic homeostasis. Whereas the role of the sympathetic nervous system (SNS) in the regulation of glucose metabolism has been fi rmly established (for review, see Ref. 9 ), considerably fewer studies have focused on its role in TG metabolism. This review provides an update specifi cally on the role of Abstract Important players in triglyceride (TG) metabolism include the liver (production), white adipose tissue (WAT) (storage), heart and skeletal muscle (combustion to generate ATP), and brown adipose tissue (BAT) (combustion toward heat), the collective action of which determine plasma TG levels. Interestingly, recent evidence points to a prominent role of the hypothalamus in TG metabolism through innervating the liver, WAT, and BAT mainly via sympathetic branches of the autonomic nervous system. Here, we review the recent fi ndings in the area of sympathetic control of TG metabolism. Various neuronal populations, such as neuropeptide Y (NPY)-expressing neurons and melanocortin-expressing neurons, as well as peripherally produced hormones (i.e., GLP-1, leptin, and insulin), modulate sympathetic outfl ow from the hypothalamus toward target organs and thereby infl uence peripheral TG metabolism. We conclude that sympathetic stimulation in general increases lipolysis in WAT, enhances VLDL-TG production by the liver, and increases the activity of BAT with respect to lipolysis of TG, followed by combustion of fatty acids toward heat. Moreover, the increased knowledge about the involvement of the neuroendocrine system in TG metabolism presented in this review offers new therapeutic options to fi ght hypertriglyceridemia by specifi cally modulating sympathetic nervous system outfl ow toward liver, BAT, or WAT .-Geerling, J. J., M. R. B...

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“…The central nervous system, and more specifically, the hypothalamus has a major regulatory role in peripheral tissue functions in health and disease (Dietrich et al, 2012; Matarese et al, 2013; Ruan et al, 2014; Warne et al, 2013). A growing body of evidence indicates that the hypothalamus also affects bone homeostasis mediated, at least in part, by the autonomic nervous system and endocrine organs (Ohlsson et al, 2012; Sato et al, 2007; Yadav et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

AgRP Neurons Regulate Bone Mass

et al. 2015

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SUMMARY The hypothalamus has been implicated in skeletal metabolism (Ducy et al., 2000; Sato et al., 2007; Yadav et al., 2009). Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known. We generated multiple lines of mice to affect AgRP neuronal circuit integrity. We found that mice with Ucp2 gene deletion, in which AgRP neuronal function was impaired, were osteopenic. This phenotype was rescued by cell-selective reactivation of Ucp2 in AgRP neurons. When the AgRP circuitry was impaired by early postnatal deletion of AgRP neurons or by cell autonomous deletion of Sirt1 (AgRP-Sirt1−/−), mice also developed reduced bone mass. No impact of leptin receptor deletion in AgRP neurons was found on bone homeostasis. Suppression of sympathetic tone in AgRP-Sirt1−/− mice reversed osteopenia in transgenic animals. Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin action.

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Coordinated Regulation of Hepatic Energy Stores by Leptin and Hypothalamic Agouti-Related Protein

Cited by 9 publications

References 84 publications

Circulating fetuin-A levels are not affected by short and long-term energy deprivation and/or by leptin administration

Circulating fetuin-A levels are not affected by short and long-term energy deprivation and/or by leptin administration

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies

AgRP Neurons Regulate Bone Mass

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