Role of Signal Transducer and Activator of Transcription 3 in Regulation of Hypothalamic Proopiomelanocortin Gene Expression by Leptin

Münzberg, Heike; Huo, Lihong; Nillni, Eduardo A.; Hollenberg, Anthony N.; Bjørbæk, Christian

doi:10.1210/en.2002-221037

Cited by 295 publications

(267 citation statements)

References 66 publications

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“…An intriguing possibility that may account for this selectivity is that leptin acts on only a subpopulation of POMC neurons, consistent with our earlier data showing that leptin activates Ϸ40% of POMC neurons (23). We therefore hypothesize that leptin may coordinately stimulate POMC expression and activate the ␣MSH N-acetylating enzyme in this subpopulation of POMC neurons without affecting the amounts or acetylation of ␣MSH in POMC cells that do not express the leptin receptor.…”

Section: Discussionsupporting

confidence: 90%

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N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin

Guo

Münzberg

Stuart

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The central melanocortin system is critical in the regulation of appetite and body weight, and leptin exerts its anorexigenic actions partly by increasing hypothalamic proopiomelanocortin (POMC) expression. The POMC-derived peptide ␣-melanocytestimulating hormone (␣MSH) is a melanocortin 4 receptor agonist, and its potency in reducing energy intake is strongly increased by N-acetylation. The reason for the higher biological activity of N-acetylated ␣MSH (Act-␣MSH) compared with that of N-desacetylated ␣MSH (Des-␣MSH) is unclear, and regulation of acetylation by leptin has not been investigated. We show here that total hypothalamic ␣MSH levels are decreased in leptin-deficient ob͞ob mice and increased in leptin-treated ob͞ob and C57BL͞6J mice. The increase in total ␣MSH occurred as soon as 3 h after leptin injection and was entirely due to an increase in Act-␣MSH. Consistent with this observation, leptin rapidly induced the enzymatic activity of a N-acetyltransferase in the hypothalamus of mice. In 293T cells expressing the melanocortin 4 receptor, Act-␣MSH is far more potent than Des-␣MSH in stimulating cAMP accumulation, an effect caused by a dramatically increased stability of Act-␣MSH. Moreover, Des-␣MSH is rapidly degraded in the hypothalamus after intracerebroventricular injection in rats and was less potent in inhibiting energy intake. The results suggest that leptin activates a N-acetyltransferase in POMC neurons, leading to increased hypothalamic levels of Act-␣MSH. Due to its increased stability, this posttranslational modification of ␣MSH may play a critical role in leptin action via the central melanocortin pathway.T he adipocyte-derived hormone leptin is expressed in fat tissue and acts on the central nervous system to inform key regulatory centers about energy stores (1-3). Leptin receptors (ObRs) are highly expressed within the hypothalamus, including in proopiomelanocortin (POMC) neurons located in the arcuate nucleus (4, 5). POMC-derived neuropeptides, primarily ␣-melanocyte-stimulating hormone (␣MSH), activate the melanocortin 4 receptor (MC4R) and function downstream of leptin signaling to regulate energy balance, although other pathways are also important (6-10). Supporting the role of the melanocortin pathway in leptin action are data showing that central injection of synthetic melanocortin receptor antagonists inhibits the effect of leptin to reduce food intake (10). Furthermore, mutations in the pomc and mc4r genes result in severe obesity in mice (6, 11) and humans (7,12).Studies investigating the regulation of POMC neurons by leptin have focused mainly on gene expression analyses. It is known that fasting, which is a state of low serum leptin levels, results in reduced amounts of POMC mRNA levels. This reduction is also seen in the hypothalamus of the leptin-deficient ob͞ob mice (13-16). In addition, hypothalamic POMC mRNA is stimulated by the administration of recombinant leptin to rodents (16). However, few studies have examined regulation of hypothalamic POMC-derived peptides, such as ...

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Section: Discussionsupporting

confidence: 90%

“…␣MSH peptides were detected in rat brain sections by immunohistochemistry as described previously (23).…”

Section: Separation Of Hypothalamic Act-␣msh and Des-␣msh By Hplcmentioning

confidence: 99%

N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin

Guo

Münzberg

Stuart

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…It is unknown whether leptin can successfully activate CNS LEPR signaling in the context of insulin deficiency. A well-established intracellular change that follows activation of LEPR signaling is the phosphorylation of STAT3 (32). Thus, to assess whether icv leptin administration triggers central LEPR signaling in insulindeficient mice, hypothalamic phosphorylated STAT3 levels were measured.…”

Section: Resultsmentioning

confidence: 99%

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Fujikawa

Chuang

Sakata

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

184

222

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Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulindeficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.brain | leptin monotherapy | glucose homeostasis | glucagon suppression A ccording to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million people in the United States alone. Regrettably, for reasons yet to be understood, the incidence of T1D has been increasing at an alarming annual rate of ∼3%, thus indicating that the number of patients with T1D is predicted to rise significantly in the future (1). T1D occurs as a consequence of pancreatic β-cell destruction leading to insulin deficiency, a defect that causes hyperglycemia, hyperglucagonemia, cachexia, ketoacidosis, and other abnormalities (2, 3). T1D is a deadly condition if not treated. Current life-saving interventions include daily insulin administration; insulin therapy reduces hyperglycemia, glycosylated hemoglobin, and cachexia and prevents or delays some T1D-associated morbidities (3, 4). However, even with insulin therapy, T1D secondary complications include debilitating and long-lasting conditions, such as heart disease, neuropathy, and hypertension (5-7). Moreover, probably because of insulin's lipogenic and cholesterologenic actions, longterm insulin treatment is suspected to underlie the increased ectopic lipid deposition (i.e., in nonadipose tissues) (8) and incidence of coronary artery disease (>90% after the age of 55 y) (9, 10) seen in patients with T1D. Furthermore, in part attributable to insulin's potent, fast-acting, glycemia-lowering effects, intensive insulin therapy significantly increases the risk for hypoglycemia, an event that is disabling and can even be fatal (3,(11...

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“…Both the primary and second-ary antisera were diluted in Tris-(hydroxymethyl)aminomethane (0.5%; Sigma) in phosphate buffer containing 0.7% seaweed gelatin (Sigma), 0.4% Triton X-100 (Sigma), and 3% BSA (Sigma), adjusted to pH 7.6. For P-STAT3 staining, or colocalization of P-STAT3 with Bcl-2, MAP2, or GFAP, the procedure developed by Munzberg et al (2003) was used with slight modification. The tissue was pretreated in 1% NaOH and 0.5-1% H 2 O 2 in H 2 O for 20 min, 0.3% glycine for 10 min, and 0.03% SDS for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Role of Signal Transducer and Activator of Transcription-3 in Estradiol-Mediated Neuroprotection

Dziennis¹,

Jia²,

Rønnekleiv³

et al. 2007

J. Neurosci.

104

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Estradiol is protective in experimental cerebral ischemia, but the precise mechanisms remain unknown. Signal transducer and activator of transcription-3 (STAT3) is a transcription factor that is activated by estrogen, translocates to the nucleus, and induces the transcription of neuroprotective genes, such as bcl-2. We determined whether estradiol increases STAT3 activation in female rat brain after focal cerebral ischemia and whether STAT3 activation contributes to estradiol-mediated neuroprotection against ischemic brain injury. Ovariectomized (OVX) female rats with and without estradiol replacement were subjected to 2 h of middle cerebral artery occlusion (MCAO), and phosphorylated STAT3 (P-STAT3) and total STAT3 (T-STAT3) were quantified by Western blot analysis at 3 and 22 h of reperfusion. STAT3 activation was colocalized with neuronal and survival markers microtubule-associated protein 2 (MAP2) and Bcl-2 using immunohistochemistry. Infarct size was measured at 22 h after MCAO in estradiol-treated OVX animals in the presence and absence of STAT3 inhibitor cucurbitacin I (JSI-124) using 2,3,5-triphenyltetrazolium chloride staining. Estradiol increased P-STAT3 in the ischemic cortex cytosolic fraction at 3 h after MCAO without affecting T-STAT3. This was associated with increased P-STAT3 in the nuclear fraction, which remained elevated at 22 h after MCAO. The nuclear P-STAT3 colocalized with MAP2 and Bcl-2 within the peri-infarct zone. The P-STAT3 inhibitor JSI-124 abolished the protective effect of estradiol without affecting infarct size in untreated OVX rats. We conclude that estradiol increases STAT3 phosphorylation in neurons after MCAO and that STAT3 activation plays an important role in estradiol-mediated neuroprotection.

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Role of Signal Transducer and Activator of Transcription 3 in Regulation of Hypothalamic Proopiomelanocortin Gene Expression by Leptin

Cited by 295 publications

References 66 publications

N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin

N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Role of Signal Transducer and Activator of Transcription-3 in Estradiol-Mediated Neuroprotection

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