Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway.

OBJECTIVES: Insulin's ability to counterbalance catecholamine-induced lipolysis defines insulin action in adipose tissue. Insulin suppresses lipolysis directly at the level of the adipocyte and indirectly through signaling in the brain. Here, we further characterized the role of brain insulin signaling in regulating lipolysis and defined the intracellular insulin signaling pathway required for brain insulin to suppress lipolysis. METHODS: We used hyperinsulinemic clamp studies coupled with tracer dilution techniques to assess insulin's ability to suppress lipolysis in two different mouse models with inducible insulin receptor depletion in all tissues (IRΔWB) or restricted to peripheral tissues excluding the brain (IRΔPER). To identify the underlying signaling pathway required for brain insulin to inhibit lipolysis, we continuously infused insulin +/- a PI3K or MAPK inhibitor into the mediobasal hypothalamus of male Sprague Dawley rats and assessed lipolysis during clamps. RESULTS: Genetic insulin receptor deletion induced marked hyperglycemia and insulin resistance in both IRΔPER and IRΔWB mice. However, the ability of insulin to suppress lipolysis was largely preserved in IRΔPER, but completely obliterated in IRΔWB mice indicating that insulin is still able to suppress lipolysis as long as brain insulin receptors are present. Blocking the MAPK, but not the PI3K pathway impaired the inhibition of lipolysis by brain insulin signaling. CONCLUSION: Brain insulin is required for insulin to suppress adipose tissue lipolysis and depends on intact hypothalamic MAPK signaling.

Central endocannabinoid signaling regulates hepatic glucose production and systemic lipolysis.

OBJECTIVE: The endocannabinoid (EC) system has been implicated as an important regulator of energy homeostasis. In obesity and type 2 diabetes, EC tone is elevated in peripheral tissues including liver, muscle, fat, and also centrally, particularly in the hypothalamus. Cannabinoid receptor type 1 (CB1) blockade with the centrally and peripherally acting rimonabant induces weight loss and improves glucose homeostasis while also causing psychiatric adverse effects. The relative contributions of peripheral versus central EC signaling on glucose homeostasis remain to be elucidated. The aim of this study was to test whether the central EC system regulates systemic glucose fluxes. RESEARCH DESIGN AND METHODS: We determined glucose and lipid fluxes in male Sprague-Dawley rats during intracerebroventricular infusions of either WIN55,212-2 (WIN) or arachidonoyl-2'-chloroethylamide (ACEA) while controlling circulating insulin and glucose levels through hyperinsulinemic, euglycemic clamp studies. Conversely, we fed rats a high-fat diet for 3 days and then blocked central EC signaling with an intracerebroventricular infusion of rimonabant while assessing glucose fluxes during a clamp. RESULTS: Central CB1 activation is sufficient to impair glucose homeostasis. Either WIN or ACEA infusions acutely impaired insulin action in both liver and adipose tissue. Conversely, in a model of overfeeding-induced insulin resistance, CB1 antagonism restored hepatic insulin sensitivity. CONCLUSIONS: Thus central EC tone plays an important role in regulating hepatic and adipose tissue insulin action. These results indicate that peripherally restricted CB1 antagonists, which may lack psychiatric side effects, are also likely to be less effective than brain-permeable CB1 antagonists in ameliorating insulin resistance.

Brain insulin controls adipose tissue lipolysis and lipogenesis.

White adipose tissue (WAT) dysfunction plays a key role in the pathogenesis of type 2 diabetes (DM2). Unrestrained WAT lipolysis results in increased fatty acid release, leading to insulin resistance and lipotoxicity, while impaired de novo lipogenesis in WAT decreases the synthesis of insulin-sensitizing fatty acid species like palmitoleate. Here, we show that insulin infused into the mediobasal hypothalamus (MBH) of Sprague-Dawley rats increases WAT lipogenic protein expression, inactivates hormone-sensitive lipase (Hsl), and suppresses lipolysis. Conversely, mice that lack the neuronal insulin receptor exhibit unrestrained lipolysis and decreased de novo lipogenesis in WAT. Thus, brain and, in particular, hypothalamic insulin action play a pivotal role in WAT functionality.

Foveolitis associated with dengue Fever: a case series.

BACKGROUND: Dengue fever (DF), a viral infection caused by dengue virus, is characterized by fever, headache, muscle and joint pains. Approximately 50-100 million people are infected annually. Ocular manifestations during DF are uncommon and include intraretinal hemorrhages and cotton wool spots; manifestations predominantly characterized by foveal involvement have not been described before in DF or any other retinopathies. We describe the clinical features of a series of patients with DF-associated foveolitis. METHODS: A retrospective review of patients with maculopathy associated with DF was conducted. Patients found to have a yellow-orange lesion at the fovea, supported by a typical optical coherence tomography (OCT) finding of disruption of the outer neurosensory retina, were analyzed. RESULTS: Ten eyes of 6 patients were studied. The mean age was 19.8 years. The mean presenting best corrected visual acuity was 6/45 (range of 6/7.5 to counting fingers). Fundus examination revealed a yellow-orange lesion at the fovea which corresponded to outer neurosensory retina disruption on OCT. Multifocal electroretinography showed decreased foveal and parafoveal responses. Treatment was variable, depended on visual acuity and ranged from observation to immunosuppression. CONCLUSION: Foveolitis may be associated with DF. OCT is a useful tool for the diagnosis and monitoring of progression of this condition.

Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms.

Leptin (encoded by Lep) controls body weight by regulating food intake and fuel partitioning. Obesity is characterized by leptin resistance and increased endocannabinoid tone. Here we show that leptin infused into the mediobasal hypothalamus (MBH) of rats inhibits white adipose tissue (WAT) lipogenesis, which occurs independently of signal transducer and activator of transcription-3 (STAT3) signaling. Correspondingly, transgenic inactivation of STAT3 signaling by mutation of the leptin receptor (s/s mice) leads to reduced adipose mass compared to db/db mice (complete abrogation of leptin receptor signaling). Conversely, the ability of hypothalamic leptin to suppress WAT lipogenesis in rats is lost when hypothalamic phosphoinositide 3-kinase signaling is prevented or when sympathetic denervation of adipose tissue is performed. MBH leptin suppresses the endocannabinoid anandamide in WAT, and, when this suppression of endocannabinoid tone is prevented by systemic CB1 receptor activation, MBH leptin fails to suppress WAT lipogenesis. These data suggest that the increased endocannabinoid tone observed in obesity is linked to a failure of central leptin signaling to restrain peripheral endocannabinoids.

Psoriasis and the eye: prevalence of eye disease in Singaporean Asian patients with psoriasis.

There is little published data on the incidence of eye disease in Asian patients with psoriasis. We determined the frequency of ocular complications in Singaporean Asian patients with chronic plaque psoriasis and related these to extent and severity of psoriasis, family history, treatment and presence of arthritis. A cross-sectional prevalence investigation was carried out in 100 patients who received a comprehensive eye examination. Psoriasis extent and severity was graded by the Lattice System Physician's Global Assessment (LS-PGA). Two patients (four eyes) had uveitis, one of whom had psoriatic arthritis (2% incidence). Presence or absence of uveitis correlated with mean LS-PGA scores. Sixty-three patients had cataract unrelated to previous steroid or phototherapy treatment; in younger (<50 years) patients they were commoner than in those with higher (>5) LS-PGA scores. Three eyes in two patients (2% prevalence) had glaucomatous optic neuropathy unrelated to previous treatment, and comparable with expected population frequency. These findings, although limited by lack of data from a comparable control population, suggest that eye complications are common in Asian patients with psoriasis and eye symptoms should be elicited during history taking. Besides signs and symptoms of eye disease, an LS-PGA score of more than 5 should prompt referral for ophthalmological examination.