Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin

Rahmouni, Kamal; Morgan, Donald A.; Morgan, Gina; Liu, Xuebo; Sigmund, Curt D.; Mark, Allyn L.; Haynes, William G.

doi:10.1172/jci21737

Cited by 170 publications

(155 citation statements)

References 45 publications

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“…A bipolar platinum-iridium electrode (Cooner Wire) was suspended under the nerve and secured with silicone gel (Kwik-Cast, WPI). The nerve signal was amplified and filtered as described previously (Rahmouni et al, 2004(Rahmouni et al, , 2008. Anesthesia was sustained with the administration of ␣-chloralose (25 mg/kg/h) intravenously.…”

Section: Methodsmentioning

confidence: 99%

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Nogueiras¹,

Pérez-Tilve²,

et al. 2009

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We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking ␤-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

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Section: Methodsmentioning

confidence: 99%

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Nogueiras¹,

Pérez-Tilve²,

et al. 2009

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“…Thirty minutes after injection of inhibitors or DMSO, animals received 33 ng/g E2 or V subcutaneously, and they were killed by an overdose of Avertin (0.015 ml/g) and perfused 15 min after E2 injection. The dose of the inhibitors and timing was established previously (Cervo et al, 1997;Han and Holtzman, 2000;Rahmouni et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

Estrogen Induces Estrogen Receptor α-Dependent cAMP Response Element-Binding Protein Phosphorylation via Mitogen Activated Protein Kinase Pathway in Basal Forebrain Cholinergic NeuronsIn Vivo

Szegő¹,

Barabás²,

Balog³

et al. 2006

J. Neurosci.

113

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In addition to classical genomic mechanisms, estrogen also exerts nonclassical effects via a signal transduction system on neurons. To study whether estrogen has a nonclassical effect on basal forebrain cholinergic system, we measured the intensity of cAMP response element-binding protein (CREB) phosphorylation (pCREB) in cholinergic neurons after administration of 17␤-estradiol to ovariectomized (OVX) mice. A significant time-dependent increase in the number of pCREB-positive cholinergic cells was detected after estrogen administration in the medial septum-diagonal band (MS-DB) and the substantia innominata (SI). The increase was first observed 15 min after estrogen administration. The role of classical estrogen receptors (ERs) was evaluated using ER knock-out mice in vivo. The estrogeninduced CREB phosphorylation in cholinergic neurons was present in ER␤ knock-out mice but completely absent in ER␣ knock-out mice in MS-DB and SI. A series of in vitro studies demonstrated that estrogen acted directly on cholinergic neurons. Selective blockade of the mitogen activated protein kinase (MAPK) pathway in vivo completely prevented estrogen-induced CREB phosphorylation in cholinergic neurons in MS-DB and SI. In contrast, blockade of protein kinase A (PKA) was effective only in SI. Finally, studies in intact female mice revealed levels of CREB phosphorylation within cholinergic neurons that were similar to those of estrogen-treated OVX mice. These observations demonstrate an ER␣-mediated nonclassical effect of estrogen on the cholinergic neurons and that these actions are present under physiological conditions. They also reveal the role of MAPK and PKA-MAPK pathway activation in nonclassical estrogen signaling in the basal forebrain cholinergic neurons in vivo.

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“…In rats, insulin, like leptin, causes sympathoactivation to different tissues, including the kidney. 27 The ability of insulin to stimulate renal sympathetic outflow is preserved in obese animals such as the db/db mice, despite the severe insulin resistance that characterizes this condition. 25 Despite these findings, a role for hyperinsulinemia and insulin resistance in obesity-associated hypertension remains controversial.…”

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confidence: 99%

Obesity-Associated Hypertension

et al. 2005

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Abstract-Obesity is strongly associated with hypertension and cardiovascular disease. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Obesity is also associated with endothelial dysfunction and renal functional abnormalities that may play a role in the development of hypertension. The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension. Better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. Other hunger and satiety signals such as ghrelin and peptide YY are potentially attractive therapeutic strategies for treatment of obesity and its complications. These recent discoveries should lead to novel strategies for treatment of obesity and hypertension. (Hypertension. 2005;45:9-14.)Key Words: hypertension, obesity Ⅲ nervous system, sympathetic renal Ⅲ vasculature Ⅲ kidney T he increasing prevalence of obesity worldwide is a serious health hazard. This is particularly true for the United States, where Ϸ300 000 deaths each year are associated with being overweight and obese. Obese individuals are at increased risk for diabetes, hypertension, renal failure, and other cardiovascular diseases. Clinical and animal studies have confirmed a strong relationship between obesity and hypertension. 1 Accumulating evidence points to visceral obesity as the most important risk factor for hypertension and cardiovascular disease. 2 Recent work has identified several mechanisms that have therapeutic implications as potential causes of obesity-hypertension. In addition, to these advances, there has also been a revolution in our understanding of neuroendocrine mechanisms regulating appetite, metabolism, and adiposity since the discovery of leptin just Ͼ10 years ago. If, as we predict, these advances soon translate into safe and effective pharmacological treatment of obesity, this would also greatly impact the management of obesityhypertension. Consequently, we briefly review some highlights on advances in understanding the pathophysiology of obesity in addition to highlights on obesity-induced hypertension. New Developments in Neurobiology of ObesityThe identification of leptin represents the most significant breakthrough in obesity research because it helped unravel the architecture of neuroendocrine circuitry that controls appetite and energy homeostasis. Leptin is an adipocyte-derived hormone that acts in the hypothalamus to regulate appetite and energy expenditure. Recently, increasing attention has been dedicated to leptin transduction mechanisms (Figure 1). The leptin receptor is a single transmembrane protein belonging to the cytokine-receptor superfamily known to signal via the janus kinase/signal ...

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Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin

Cited by 170 publications

References 45 publications

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Estrogen Induces Estrogen Receptor α-Dependent cAMP Response Element-Binding Protein Phosphorylation via Mitogen Activated Protein Kinase Pathway in Basal Forebrain Cholinergic NeuronsIn Vivo

Obesity-Associated Hypertension

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