Cushing's disease with twin pregnancy and diabetes mellitus: a case report and literature review.

A 38-year-old Japanese woman with a history of abnormal thyroid function of non-autoimmune origin, pituitary endocrine tumor, and untreated diabetes mellitus was referred to our outpatient clinic when she became pregnant with twins. Physical findings consistent with Cushing's syndrome (CS) were absent at the time of presentation. Although baseline plasma adrenocorticotropic hormone, serum cortisol, and 24-hour urinary free cortisol excretion levels were above the upper limits of normal non-pregnant reference ranges, we could not exclude a physiological increase associated with pregnancy. No medical or surgical intervention for hypercortisolism was performed during pregnancy. Spontaneous vaginal delivery resulted in the normal delivery of live twins. A diagnosis of Cushing's disease (CD) was established when papery skin developed postpartum. Transsphenoidal surgery was performed and the hypercortisolism partially resolved post-operatively. The patient's abnormal thyroid function also resolved. Pregnancy in women with endogenous CS is rare, with less than 300 cases reported. Most reported cases of CS during pregnancy are of adrenal origin. Only two cases of twin pregnancies with CD have been reported. Therefore, we reported the third case of CD in a twin pregnancy and reviewed the diagnostic and therapeutic challenges associated with CD during pregnancy.

Mitogen-activated protein kinase phosphatase 1 negatively regulates MAPK signaling in mouse hypothalamus.

Mitogen-activated protein kinase phosphatase 1 (MKP-1) is shown to negatively regulate MAPK signaling in various peripheral tissues as well as the central nervous system such as cortex, striatum and hippocampus. In this study, we examined whether MKP-1 regulates MAPK signaling in the mouse hypothalamus. Intraperitoneal injection of TNFα significantly increased MKP-1 mRNA expression in paraventricular and arcuate nuclei in the hypothalamus. TNFα treatment induced increases in MKP-1 expression at both mRNA and protein levels, accompanied by the inactivation of MAPK signaling in mouse hypothalamic explants. Inhibition of MKP-1 by its inhibitor or siRNA increased MAPK activity in the explants. Our data indicate that MKP-1 negatively regulates MAPK signaling in the mouse hypothalamus.

GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet.

There is evidence suggesting that the GABA system in the arcuate nucleus, where orexigenic neuropeptide Y and agouti-related peptide as well as anorexigenic proopiomelanocortin (POMC) are expressed, plays an important role in energy balance. In this study, we generated POMC-specific GABAB receptor-deficient [knock-out (KO)] mice. Male KO mice on a high-fat diet (HFD) showed mild increases in body weight (BW) at the age of 9 weeks compared to wild-type (WT) mice, and the differences remained significant until 16 weeks old. However, there was no difference in BW in females between genotypes. While food intake was similar between genotypes, oxygen consumption was significantly decreased in the male KO mice. The insulin tolerance test revealed that the male KO mice were less insulin sensitive compared to WT mice at the age of 8 weeks, when there was no significant difference in BW between genotypes. Despite increased BW, POMC mRNA expression in the arcuate nucleus was significantly decreased in the KO mice compared to WT mice at the age of 16 weeks. Furthermore, the expression of TNFα as well as IL-6, proinflammatory markers in the hypothalamus, was significantly increased in the KO mice on a HFD compared to WT mice. This demonstrates that the deletion of GABAB receptors in POMC neurons in the male mice on a HFD results in obesity, insulin resistance, and hypothalamic inflammation. Furthermore, the decreased POMC expression in the obese KO mice suggests that the regulation of POMC expression through GABAB receptors is essential for proper energy balance.

Expression of neuropeptide Y and agouti-related protein mRNA stimulated by glucocorticoids is attenuated via NF-κB p65 under ER stress in mouse hypothalamic cultures.

There are several lines of evidence suggesting that glucocorticoid signaling in the hypothalamus plays an important role in energy balance, and recent studies suggest that endoplasmic reticulum (ER) stress in the hypothalamus could affect signaling related to energy balance. In the present study, we examined the regulation of glucocorticoid signaling under ER stress in mouse hypothalamic organotypic cultures. Incubation of the hypothalamic explants with dexamethasone (DEX) significantly increased expression levels of neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA, and treatment with thapsigargin (TG), an ER stressor, significantly attenuated DEX-induced NPY and AgRP mRNA expression. TG treatment increased the levels of phospho-NF-κB p65 in hypothalamic cultures, and inhibitors of NF-κB p65 reversed the inhibitory effects of TG on NPY and AgRP expression. Our data thus demonstrated that glucocorticoid-stimulated NPY and AgRP expression was attenuated via NF-κB p65 pathways under ER stress, and suggest crosstalk between ER stress and inflammation in the hypothalamus.

TNFα increases hypothalamic PTP1B activity via the NFκB pathway in rat hypothalamic organotypic cultures.

In obesity, levels of tumor necrosis-factor α (TNFα) are well known to be elevated in adipose tissues or serum, and a high-fat diet (HFD) reportedly increases TNFα expression in the hypothalamus. The expression levels of hypothalamic protein tyrosine phosphatase 1B (PTP1B), a negative regulator of leptin and insulin signaling, are also elevated by HFD, and several lines of evidence support a relationship between TNFα and PTP1B. It remains unclear however how TNFα acts locally in the hypothalamus to regulate hypothalamic PTP1B expression and activity. In this study, we examined whether TNFα can regulate PTP1B expression and activity using rat hypothalamic organotypic cultures. Incubation of cultures with TNFα resulted in increases in mRNA expression, protein levels and activity of PTP1B in a dose- and time-dependent manner, respectively compared with controls. TNFα-induced PTP1B protein levels were not influenced by co-incubation with the sodium channel blocker tetrodotoxin, indicating that the action of TNFα is independent of action potentials. TNFα also increased phosphorylation of p65, a subunit of nuclear factor-κB (NFκB), in a dose- and time-dependent manner. While incubation with inhibitors of NFκB did not affect basal levels of either p65 phosphorylation or PTP1B expression, it markedly suppressed both TNFα-induced p65 phosphorylation and PTP1B expression to almost basal levels. These data suggest that TNFα acts on the hypothalamus to increase hypothalamic PTP1B expression and activity via the NFκB pathway, and that TNFα-mediated induction of NFκB in the hypothalamus may cause leptin and insulin resistance in the hypothalamus by increasing hypothalamic PTP1B activity.