LKB1 up-regulation inhibits hypothalamic inflammation and attenuates diet-induced obesity in mice.

BACKGROUND: Diet-induced obesity (DIO) is associated with chronic, low-grade inflammation in the hypothalamus. The inflammatory pathway of the hypothalamus is activated during obesity, and inhibition of activation of the inflammatory pathway can partially reverse obesity. Therefore, exploring new targets for inhibiting hypothalamic inflammation will provide new ideas for the prevention and treatment of obesity. Liver kinase B1 (LKB1), a serine/threonine kinase, is a tumor suppressor and metabolic regulator. Recent studies have shown that LKB1 has a certain anti-inflammatory effect. However, a role of LKB1 in the regulation of hypothalamic inflammation remains unclear. Therefore, we examined whether LKB1 overexpression in the hypothalamus could weaken the hypothalamic inflammation and inhibit the development of obesity. METHODS: LKB1 overexpressing adeno-associated virus (AAV) particles were injected stereotactically into the third ventricle (3 V) of C57BL/6 mice fed with HFD. We assessed changes in body mass and adiposity, food intake, hypothalamic inflammatory markers, and energy and glucose metabolism. RESULTS: LKB1 up-regulation in hypothalamus attenuated diet-induced hypothalamic inflammation, reduced food intake and body weight gain. In addition, the overexpression of hypothalamic LKB1 increased the insulin sensitivity and improved whole-body lipid metabolism, which attenuated hepatic fat accumulation and serum lipid levels. CONCLUSION: Hypothalamic LKB1 up-regulation attenuates hypothalamic inflammation, and protects against hypothalamic inflammation induced damage to melanocortin system, resulting in lower food intake and lower fat mass accumulation, which consequently protects mice from the development of obesity. Our data suggest LKB1 as a novel negative regulator of hypothalamic inflammation, and also a potentially important target for treating other inflammatory diseases.

Propentofylline decreases hypothalamic astrogliosis induced by hypercaloric diet in the rat.

Obesity is associated with a chronic and low-grade inflammatory response in the hypothalamus, where astrogliosis occurs with the upregulation of the astrocyte structural protein GFAP. As propentofylline (PPF) has inhibitory effects on astrocyte and microglial activation during inflammation, this study aimed to investigate if this xanthine derivative could decrease the astrocyte reaction induced by a hypercaloric diet (HD). Male Wistar rats were divided into four groups: NDS - rats receiving a normocaloric diet (ND) and daily saline solution; NDP - rats receiving ND and daily PPF (12.5 mg/kg/day, intraperitoneal route); HDS - rats receiving HD and saline solution, HDP - rats receiving HD and PPF. On the 21st day, rats were anesthetized, and perfused, and brains were collected for GFAP immunohistochemical study in the hypothalamus. Results showed that HD induced increased weight gain and hypothalamic astrogliosis. Propentofylline decreased the expression of GFAP in the HDP group, although it did not affect the weight gain induced by this diet.

Propentofylline decreases hypothalamic astrogliosis induced by hypercaloric diet in the rat / A propentofilina diminui a astrogliose hipotalâmica induzida pela dieta hipercalórica no rato

ABSTRACT Obesity is associated with a chronic and low-grade inflammatory response in the hypothalamus, where astrogliosis occurs with the upregulation of the astrocyte structural protein GFAP. As propentofylline (PPF) has inhibitory effects on astrocyte and microglial activation during inflammation, this study aimed to investigate if this xanthine derivative could decrease the astrocyte reaction induced by a hypercaloric diet (HD). Male Wistar rats were divided into four groups: NDS - rats receiving a normocaloric diet (ND) and daily saline solution; NDP - rats receiving ND and daily PPF (12.5 mg/kg/day, intraperitoneal route); HDS - rats receiving HD and saline solution, HDP - rats receiving HD and PPF. On the 21st day, rats were anesthetized, and perfused, and brains were collected for GFAP immunohistochemical study in the hypothalamus. Results showed that HD induced increased weight gain and hypothalamic astrogliosis. Propentofylline decreased the expression of GFAP in the HDP group, although it did not affect the weight gain induced by this diet.

RESUMO A obesidade está associada com uma resposta inflamatória crônica e de baixo grau no hipotálamo, onde ocorre astrogliose com a superexpressão da proteína astrocitária GFAP. Como a propentofilina (PPF) possui efeitos inibitórios sobre a ativação astrocitária e microglial durante a inflamação, este estudo visou a investigar se esta xantina podia diminuir a reação astrocitária induzida pela dieta hipercalórica (HD). Ratos Wistar machos foram divididos em 4 grupos: NDS- ratos recebendo dieta normocalórica (ND) e solução salina diária; NDP- ratos recebendo ND e PPF diária (12.5 mg/kg/dia, via intraperitoneal); HDS- ratos recebendo HD e solução salina, HDP- ratos recebendo HD e PPF. No 21° dia, os ratos foram perfundidos e os encéfalos, coletados para estudo imuno-histoquímico para a GFAP no hipotálamo. Os resultados mostram que a HD induziu aumento do ganho de peso e astrogliose no hipotálamo. A PPF diminuiu a expressão de GFAP no grupo HD, embora não tenha afetado o ganho de peso induzido por esta dieta.

Early intervention with intranasal NPY prevents single prolonged stress-triggered impairments in hypothalamus and ventral hippocampus in male rats.

Intranasal administration of neuropeptide Y (NPY) is a promising treatment strategy to reduce traumatic stress-induced neuropsychiatric symptoms of posttraumatic stress disorder (PTSD). We evaluated the potential of intranasal NPY to prevent dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, a core neuroendocrine feature of PTSD. Rats were exposed to single prolonged stress (SPS), a PTSD animal model, and infused intranasally with vehicle or NPY immediately after SPS stressors. After 7 days undisturbed, hypothalamus and hippocampus, 2 structures regulating the HPA axis activity, were examined for changes in glucocorticoid receptor (GR) and CRH expression. Plasma ACTH and corticosterone, and hypothalamic CRH mRNA, were significantly higher in the vehicle but not NPY-treated group, compared with unstressed controls. Although total GR levels were not altered in hypothalamus, a significant decrease of GR phosphorylated on Ser232 and increased FK506-binding protein 5 mRNA were observed with the vehicle but not in animals infused with intranasal NPY. In contrast, in the ventral hippocampus, only vehicle-treated animals demonstrated elevated GR protein expression and increased GR phosphorylation on Ser232, specifically in the nuclear fraction. Additionally, SPS-induced increase of CRH mRNA in the ventral hippocampus was accompanied by apparent decrease of CRH peptide particularly in the CA3 subfield, both prevented by NPY. The results show that early intervention with intranasal NPY can prevent traumatic stress-triggered dysregulation of the HPA axis likely by restoring HPA axis proper negative feedback inhibition via GR. Thus, intranasal NPY has a potential as a noninvasive therapy to prevent negative effects of traumatic stress.

Hypothalamic gliosis associated with high-fat diet feeding is reversible in mice: a combined immunohistochemical and magnetic resonance imaging study.

Gliosis, the activation of astrocyte and microglial cell populations, is a hallmark of central nervous system injury and is detectable using either immunohistochemistry or in vivo magnetic resonance imaging (MRI). Obesity in rodents and humans is associated with gliosis of the arcuate nucleus, a key hypothalamic region for the regulation of energy homeostasis and adiposity, but whether this response is permanent or reversible is unknown. Here we combine terminal immunohistochemistry analysis with serial, noninvasive MRI to characterize the progression and reversibility of hypothalamic gliosis in high-fat diet (HFD)-fed mice. The effects of HFD feeding for 16 weeks to increase body weight and adiposity relative to chow were nearly normalized after the return to chow feeding for an additional 4 weeks in the diet-reversal group. Mice maintained on the HFD for the full 20-week study period experienced continued weight gain associated with the expected increases of astrocyte and microglial activation in the arcuate nucleus, but these changes were not observed in the diet-reversal group. The proopiomelanocortin neuron number did not differ between groups. Although MRI demonstrated a positive correlation between body weight, adiposity, and the gliosis-associated T2 signal in the mediobasal hypothalamus, it did not detect the reversal of gliosis among the HFD-fed mice after the return to chow diet. We conclude that hypothalamic gliosis associated with 16-week HFD feeding is largely reversible in rodents, consistent with the reversal of the HFD-induced obesity phenotype, and extend published evidence regarding the utility of MRI as a tool for studying obesity-associated hypothalamic gliosis in vivo.

Icariin attenuates chronic mild stress-induced dysregulation of the LHPA stress circuit in rats.

Chronic mild stress (CMS) is suggested to develop dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) stress circuit. Icariin, a major constituent of flavonoids isolated from Epimedium brevicornum, has been previously confirmed to rescue the HPA axis abnormalities in animal models of depression. However, antidepressant treatment of icariin on corticotropin-releasing factor (CRF) system within the LHPA stress circuit and its interaction with serotonergic receptor are still seldom studied in CMS model of animals. The present study further investigated the effects of CMS procedure and subsequent icariin treatment on mRNA and protein levels of CRF, CRF receptor 1 (CRFR1) and CRF binding protein (CRFBP), as well as sucrose intake in rats. Moreover, the levels of cyclic adenosine 3',5'-monophosphate (cAMP) response element binding protein (CREB), glucocorticoid receptor (GR) and 5-hydroxytryptamine 1A receptor (5-HTR1A) in hypothalamus, hippocampus and frontal cortex were simultaneously evaluated for their participations in CRF system in this model. We found that CMS procedure significantly increased CRF expression levels in the brain regions, and decreased GR and 5-HTR1A in hippocampus and frontal cortex, with sucrose intake reduction representing the hedonic deficit in rats. Icariin restored these alterations in CMS rats. These results confirmed the hypothesis that icariin exerted antidepressant-like effect via its regulation of central CRF system. And hippocampus was suggested as an important neural area controlling the LHPA stress circuit in icariin-treated CMS rats. These findings for the first time proved that the potential molecular mechanism of antidepressant action of icariin was targeted on the interaction of the LHPA stress circuit and serotonergic function in CMS rats.

A multimodality approach to the treatment of craniopharyngiomas avoiding hypothalamic morbidity: a UK perspective.

The management of craniopharyngiomas is complex and controversial. The perception that they are benign tumours cured by radical surgical resection is not borne out by their often difficult excision, propensity to recur and invade, and high late morbidity and mortality from direct brain injury. Their central location makes visual or pituitary dysfunction and/or hydrocephalus common presenting features. The most important consequence of craniopharyngiomas is hypothalamic injury which may result in severe, crippling and life-threatening sequelae, such as adipsia, morbid obesity, sleep, and behavioural and cognitive disorders. Evidence suggests that unless the tumour is smaller than 2-4 cm in the mid-line and completely resectable without additional hypothalamic or visual compromise, the surgical approach should be conservative even if this leaves residual tumour. Adjuvant focal radiotherapy to residual or recurrent disease has proven efficacy in long-term tumour control. Thus concerns regarding the potential late toxicity of radiotherapy to the developing brain need to be balanced against the recognised morbidity and mortality of recurrent tumour and repeated neurosurgical interventions. Hypothalamic damage is in many cases surgically induced. Given the devastating consequences of such an injury this should be avoided at all costs. Thus the aims of primary treatment should be to relieve tumour-associated compression symptoms, preserve (or improve) vision and hypothalamo-pituitary function, and minimise tumour recurrence with its attendant high morbidity and mortality. National registration and management by multidisciplinary teams in specialised centres according to nationally agreed risk adapted treatment strategies are likely to improve outcomes, as has been demonstrated for example in adult pituitary tumours. Because of the rarity of craniopharyngiomas, international collaborative trials are necessary to properly inform future therapies.

The present and future management of childhood craniopharyngioma.

Childhood craniopharyngiomas are rare tumours that present formidable difficulties in their treatment if cure is to be achieved without producing severe hypothalamic damage. Experience with our own cases suggests that the morbidity from an attempted radical removal can be predicted - allowing a treatment algorithm to be devised that combines both surgery (radical and "conservative") and radiotherapy (both external fractionated and intra-cyst instillations) in order to achieve long-term tumour control that is not at the expense of a severe functional disability.