Evaluating the Impact of Inadequate Meal Consumption on Insulin-Related Hypoglycemia in Hospitalized Patients.

OBJECTIVE: Meal intake is sometimes reduced in hospitalized patients. Meal-time insulin administration can cause hypoglycemia when a meal is not consumed. Inpatient providers may avoid ordering meal-time insulin due to hypoglycemia concerns, which can result in hyperglycemia. The frequency of reduced meal intake in hospitalized patients remains inadequately determined. This quality improvement project evaluates the percentage of meals consumed by hospitalized patients with insulin orders and the resulting risk of postmeal hypoglycemia (blood glucose [BG] <70 mg/dL, <3.9 mmol/L). METHODS: This was a retrospective quality improvement project evaluating patients with any subcutaneous insulin orders hospitalized at a regional academic medical center between 2015 and 2017. BG, laboratory values, point of care, insulin administration, diet orders, and percentage of meal consumed documented by registered nurses were abstracted from electronic health records. RESULTS: Meal consumption ≥50% was observed for 85% of meals with insulin orders, and bedside registered nurses were accurate at estimating this percentage. Age ≥65 years was a risk factor for reduced meal consumption (21% of meals 0%-49% consumed, P < .05 vs age < 65 years [12%]). Receiving meal-time insulin and then consuming only 0% to 49% of a meal (defined here as a mismatch) was not rare (6% of meals) and increased postmeal hypoglycemia risk. However, the attributable risk of postmeal hypoglycemia due to this mismatch was low (4 events per 1000) in patients with premeal BG between 70 and 180 mg/dL. CONCLUSION: This project demonstrates that hospitalized patients treated with subcutaneous insulin have a low attributable risk of postmeal hypoglycemia related to inadequate meal intake.

Validation of an equation for energy expenditure that does not require the respiratory quotient.

BACKGROUND: Energy expenditure (EE) calculated from respirometric indirect calorimetry is most accurate when based on oxygen consumption (VO2), carbon dioxide production (VCO2) and estimated protein metabolism (PM). EE has a substantial dependence of ~7% on the respiratory quotient (RQ, VCO2/VO2) and a lesser dependence on PM, yet many studies have instead estimated EE from VO2 only while PM has often been ignored, thus reducing accuracy. In 1949 Weir proposed a method to accurately calculate EE without using RQ, which also adjusts for estimated PM based on dietary composition. This RQ- method utilizes the calorimeter airflow rate (FR), the change in fractional O2 concentration (ΔFO2) and the dietary protein fraction. The RQ- method has not previously been empirically validated against the standard RQ+ method using both VO2 and RQ. Our aim was to do that. METHODS: VO2 and VCO2 were measured repeatedly in 8 mice fed a high protein diet (HPD) during exposure to different temperatures (n = 168 measurements of 24h gas exchange). The HPD-adjusted RQ+ equation was: EE [kcal/time] = VO2 [L/time]×(3.853+1.081RQ) while the corresponding RQ- equation was: EE = 4.934×FR×ΔFO2. Agreement was analyzed using the ratios of the RQ- to RQ+ methods along with regression and Bland-Altman agreement analyses. We also evaluated the standard equation using the dietary food quotient (FQ) of 0.91 as a proxy for RQ (FQ+ method). RESULTS: Ratio analysis revealed that the mean error of the RQ- method was only 0.11 ± 0.042% while the maximum error was only 0.21%. Error using the FQ+ method was 4 -and 10-fold greater, respectively. Bland-Altman analysis demonstrated that the RQ- method very slightly overestimates EE as RQ decreases. Theoretically, this error can be eliminated completely by imposing an incurrent fractional oxygen concentration at a value only slightly greater than the atmospheric level. CONCLUSIONS: The Weir 'RQ-free' method for calculating EE is a highly valid alternative to the 'gold standard' method that requires RQ. The RQ- approach permits reduced cost and complexity in studies focused on EE and provides a way to rescue EE measurement in studies compromised by faulty CO2 measurements. Practitioners of respirometry should consider adjusting EE calculations for estimated protein metabolism based on dietary composition.

What Can We Learn From Point-of-Care Blood Glucose Values Deleted and Repeated by Nurses?

BACKGROUND: Hospitals rely on point-of-care (POC) blood glucose (BG) values to guide important decisions related to insulin administration and glycemic control. Evaluation of POC BG in hospitalized patients is associated with measurement and operator errors. Based on a previous quality improvement (QI) project we introduced an option for operators to delete and repeat POC BG values suspected as erroneous. The current project evaluated our experience with deleted POC BG values over a 2-year period. METHOD: A retrospective QI project included all patients hospitalized at two regional academic medical centers in the Pacific Northwest during 2014 and 2015. Laboratory Medicine POC BG data were reviewed to evaluate all inpatient episodes of deleted and repeated POC BG. RESULTS: Inpatient operators choose to delete and repeat only 0.8% of all POC BG tests. Hypoglycemic and extreme hyperglycemic BG values are more likely to be deleted and repeated. Of initial values <40 mg/dL, 58% of deleted values (18% of all values) are errors. Of values >400 mg/dL, 40% of deleted values (5% of all values) are errors. Not all repeated POC BG values are first deleted. Optimal use of the option to delete and repeat POC BG values <40 mg/dL could decrease reported rates of severe hypoglycemia by as much as 40%. CONCLUSIONS: This project demonstrates that operators are frequently able to identify POC BG values that are measurement/operator errors. Eliminating these errors significantly reduces documented rates of severe hypoglycemia and hyperglycemia, and has the potential to improve patient safety.

Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus.

Anorexia is a common manifestation of chronic diseases, including cancer. Here we investigate the contribution to cancer anorexia made by calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) that transmit anorexic signals. We show that CGRPPBN neurons are activated in mice implanted with Lewis lung carcinoma cells. Inactivation of CGRPPBN neurons before tumor implantation prevents anorexia and loss of lean mass, and their inhibition after symptom onset reverses anorexia. CGRPPBN neurons are also activated in Apcmin/+ mice, which develop intestinal cancer and lose weight despite the absence of reduced food intake. Inactivation of CGRPPBN neurons in Apcmin/+ mice permits hyperphagia that counteracts weight loss, revealing a role for these neurons in a 'nonanorexic' cancer model. We also demonstrate that inactivation of CGRPPBN neurons prevents lethargy, anxiety and malaise associated with cancer. These findings establish CGRPPBN neurons as key mediators of cancer-induced appetite suppression and associated behavioral changes.

Perioperative Glycemic Control During Colorectal Surgery.

Hyperglycemia occurs frequently among patients undergoing colorectal surgery and is associated with increased risk of poor clinical outcomes, especially related to surgical site infections. Treating hyperglycemia has become a target of many enhanced recovery after surgery programs developed for colorectal procedures. There are several unique considerations for patients undergoing colorectal surgery including bowel preparations and alterations in oral intake. Focused protocols for those with diabetes and those at risk of hyperglycemia are needed in order to address the specific needs of those undergoing colorectal procedures.

Point-of-care blood glucose measurement errors overestimate hypoglycaemia rates in critically ill patients.

BACKGROUND: Hypoglycaemia is associated with morbidity and mortality in critically ill patients, and many hospitals have programmes to minimize hypoglycaemia rates. Recent studies have established the hypoglycaemic patient-day as a key metric and have published benchmark inpatient hypoglycaemia rates on the basis of point-of-care blood glucose data even though these values are prone to measurement errors. METHODS: A retrospective, cohort study including all patients admitted to Harborview Medical Center Intensive Care Units (ICUs) during 2010 and 2011 was conducted to evaluate a quality improvement programme to reduce inappropriate documentation of point-of-care blood glucose measurement errors. Laboratory Medicine point-of-care blood glucose data and patient charts were reviewed to evaluate all episodes of hypoglycaemia. RESULTS: A quality improvement intervention decreased measurement errors from 31% of hypoglycaemic (<70 mg/dL) patient-days in 2010 to 14% in 2011 (p < 0.001) and decreased the observed hypoglycaemia rate from 4.3% of ICU patient-days to 3.4% (p < 0.001). Hypoglycaemic events were frequently recurrent or prolonged (~40%), and these events are not identified by the hypoglycaemic patient-day metric, which also may be confounded by a large number of very low risk or minimally monitored patient-days. CONCLUSIONS: Documentation of point-of-care blood glucose measurement errors likely overestimates ICU hypoglycaemia rates and can be reduced by a quality improvement effort. The currently used hypoglycaemic patient-day metric does not evaluate recurrent or prolonged events that may be more likely to cause patient harm. The monitored patient-day as currently defined may not be the optimal denominator to determine inpatient hypoglycaemic risk.

Efficacy of diabetes nurse expert team program to improve nursing confidence and expertise in caring for hospitalized patients with diabetes mellitus.

Nursing care for hospitalized patients with diabetes has become more complex as evidence accumulates that inpatient glycemic control improves outcomes. Previous studies have highlighted challenges for educators in providing inpatient diabetes education to nurses. In this article, the authors show that a unit-based diabetes nurse expert team model, developed and led by a diabetes clinical nurse specialist, effectively increased nurses' confidence and expertise in inpatient diabetes care. Adapting this model in other institutions may be a cost-effective way to improve inpatient diabetes care and safety as well as promote professional growth of staff nurses.

Evaluation of point-of-care blood glucose measurements in patients with diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome admitted to a critical care unit.

BACKGROUND: Point-of-care (POC) blood glucose (BG) measurement is currently not recommended in the treatment of patients presenting with diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar syndrome (HHS). METHODS: We prospectively evaluated and compared capillary and venous POC BG values with laboratory venous glucose in patients with DKA or HHS admitted to one critical care unit over 8 months. RESULTS: Venous laboratory glucose was strongly correlated with venous (r = 0.98) and capillary (r = 0.96) POC glucose values, though POC glucose values were higher than venous laboratory values (venous POC 21 ± 3 mg/dl, capillary POC 30 ± 4 mg/dl; both p < .001). Increased plasma osmolality had no effect on glucose meter error, while acidemia (pH < 7.3) was associated with greater glucose meter error (p = .04) independent of glucose levels. Comparing hypothetical insulin infusion rates based on laboratory venous glucose to actual infusion rates based on POC glucose values showed that 33/61 insulin infusion rates would have been unchanged, while 28 out of 61 rates were on average 7% ± 2% higher. There were no instances of hypoglycemia in any of the patients. CONCLUSIONS: Overall, both venous and capillary POC BG values were safe for the purpose of titrating insulin infusions in patients with severe hyperglycemia. Acidemia, but not hyperosmolality, increased POC BG value errors.

In uncontrolled diabetes, thyroid hormone and sympathetic activators induce thermogenesis without increasing glucose uptake in brown adipose tissue.

Recent advances in human brown adipose tissue (BAT) imaging technology have renewed interest in the identification of BAT activators for the treatment of obesity and diabetes. In uncontrolled diabetes (uDM), activation of BAT is implicated in glucose lowering mediated by intracerebroventricular (icv) administration of leptin, which normalizes blood glucose levels in streptozotocin (STZ)-induced diabetic rats. The potent effect of icv leptin to increase BAT glucose uptake in STZ-diabetes is accompanied by the return of reduced plasma thyroxine (T4) levels and BAT uncoupling protein-1 (Ucp1) mRNA levels to nondiabetic controls. We therefore sought to determine whether activation of thyroid hormone receptors is sufficient in and of itself to lower blood glucose levels in STZ-diabetes and whether this effect involves activation of BAT. We found that, although systemic administration of the thyroid hormone (TR)ß-selective agonist GC-1 increases energy expenditure and induces further weight loss in STZ-diabetic rats, it neither increased BAT glucose uptake nor attenuated diabetic hyperglycemia. Even when GC-1 was administered in combination with a ß(3)-adrenergic receptor agonist to mimic sympathetic nervous system activation, glucose uptake was not increased in STZ-diabetic rats, nor was blood glucose lowered, yet this intervention potently activated BAT. Similar results were observed in animals treated with active thyroid hormone (T3) instead of GC-1. Taken together, our data suggest that neither returning normal plasma thyroid hormone levels nor BAT activation has any impact on diabetic hyperglycemia, and that in BAT, increases of Ucp1 gene expression and glucose uptake are readily dissociated from one another in this setting.

BDNF action in the brain attenuates diabetic hyperglycemia via insulin-independent inhibition of hepatic glucose production.

Recent evidence suggests that central leptin administration fully normalizes hyperglycemia in a rodent model of uncontrolled insulin-deficient diabetes by reducing hepatic glucose production (HGP) and by increasing glucose uptake. The current studies were undertaken to determine whether brain-derived neurotrophic factor (BDNF) action in the brain lowers blood glucose in uncontrolled insulin-deficient diabetes and to investigate the mechanisms mediating this effect. Adult male rats implanted with cannulas to either the lateral cerebral ventricle or the ventromedial hypothalamic nucleus (VMN) received either vehicle or streptozotocin to induce uncontrolled insulin-deficient diabetes. Three days later, animals received daily intracerebroventricular or intra-VMN injections of either BDNF or its vehicle. We found that repeated daily intracerebroventricular administration of BDNF attenuated diabetic hyperglycemia independent of changes in food intake. Instead, using tracer dilution techniques during a basal clamp, we found that BDNF lowered blood glucose levels by potently suppressing HGP, without affecting tissue glucose uptake, an effect associated with normalization of both plasma glucagon levels and hepatic expression of gluconeogenic genes. Moreover, BDNF microinjection directly into the VMN also lowered fasting blood glucose levels in uncontrolled insulin-deficient diabetes, but this effect was modest compared with intracerebroventricular administration. We conclude that central nervous system BDNF attenuates diabetic hyperglycemia via an insulin-independent mechanism. This action of BDNF likely involves the VMN and is associated with inhibition of glucagon secretion and a decrease in the rate of HGP.

Lipopolysaccharide-induced lung injury is independent of serum vitamin D concentration.

Vitamin D deficiency is increasing in incidence around the world. Vitamin D, a fat-soluble vitamin, has documented effects on the innate and adaptive immune system, including macrophage and T regulatory (Treg) cell function. Since Treg cells are important in acute lung injury resolution, we hypothesized that vitamin D deficiency increases the severity of injury and delays injury resolution in lipopolysaccharide (LPS) induced acute lung injury. Vitamin D deficient mice were generated, using C57BL/6 mice, through diet modification and limited exposure to ultraviolet light. At 8 weeks of age, vitamin D deficient and sufficient mice received 2.5 g/kg of LPS or saline intratracheal. At 1 day, 3 days and 10 days, mice were anesthetized and lung elastance measured. Mice were euthanized and bronchoalveolar lavage fluid, lungs and serum were collected. Ex vivo neutrophil chemotaxis was evaluated, using neutrophils from vitamin D sufficient and deficient mice exposed to the chemoattractants, KC/CXCL1 and C5a, and to bronchoalveolar lavage fluid from LPS-exposed mice. We found no difference in the degree of lung injury. Leukocytes were mildly decreased in the bronchoalveolar fluid of vitamin D deficient mice at 1 day. Ex-vivo, neutrophils from vitamin D deficient mice showed impaired chemotaxis to KC but not to C5a. Vitamin D deficiency modestly impairs neutrophil chemotaxis; however, it does not affect lung injury or its resolution in an LPS model of acute lung injury.

Acutely decreased thermoregulatory energy expenditure or decreased activity energy expenditure both acutely reduce food intake in mice.

Despite the suggestion that reduced energy expenditure may be a key contributor to the obesity pandemic, few studies have tested whether acutely reduced energy expenditure is associated with a compensatory reduction in food intake. The homeostatic mechanisms that control food intake and energy expenditure remain controversial and are thought to act over days to weeks. We evaluated food intake in mice using two models of acutely decreased energy expenditure: 1) increasing ambient temperature to thermoneutrality in mice acclimated to standard laboratory temperature or 2) exercise cessation in mice accustomed to wheel running. Increasing ambient temperature (from 21 °C to 28 °C) rapidly decreased energy expenditure, demonstrating that thermoregulatory energy expenditure contributes to both light cycle (40 ± 1%) and dark cycle energy expenditure (15 ± 3%) at normal ambient temperature (21 °C). Reducing thermoregulatory energy expenditure acutely decreased food intake primarily during the light cycle (65 ± 7%), thus conflicting with the delayed compensation model, but did not alter spontaneous activity. Acute exercise cessation decreased energy expenditure only during the dark cycle (14 ± 2% at 21 °C; 21 ± 4% at 28 °C), while food intake was reduced during the dark cycle (0.9 ± 0.1 g) in mice housed at 28 °C, but during the light cycle (0.3 ± 0.1 g) in mice housed at 21 °C. Cumulatively, there was a strong correlation between the change in daily energy expenditure and the change in daily food intake (R(2) = 0.51, p<0.01). We conclude that acutely decreased energy expenditure decreases food intake suggesting that energy intake is regulated by metabolic signals that respond rapidly and accurately to reduced energy expenditure.

The impact of inpatient point-of-care blood glucose quality control testing.

Analyze the effectiveness of mandated point-of-care (POC) blood glucose (BG) meter quality control (QC) testing. All POC BG QC tests were analyzed to evaluate operator and strip/meter error rates and institutional cost. POC BG QC test failure (17/103,580 over 24 months) was low and no meters failed subsequent linearity testing. Examining individual QC measures shows that operator error occurs frequently and total error rate is related to QC familiarity (>50 QC tests/month, 2.4%; <50 QC tests/month, 3.8%, p < .001). Even among the most competent operators, strip/meter error (1.2 ± 0.3%) accounted for 50% of total error. Compared with manufacturer-recommended QC testing, Joint Commission mandated POC BG QC testing during 2008/2009 incurred excess costs of approximately US$127,000. POC BG meter failure within current guidelines is rare and does not justify the cost of daily QC testing. Frequent QC testing can identify operators needing retraining in POC testing. Strip/meter QC errors are common, are not prevented by current QC testing standards, and may contribute to clinical errors.

Obesity is associated with hypothalamic injury in rodents and humans.

Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.

Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice.

Myostatin deficiency causes dramatically increased skeletal muscle mass and reduced fat mass. Previously, myostatin-deficient mice were reported to have unexpectedly low total energy expenditure (EE) after normalizing to body mass, and thus, a metabolic cause for low fat mass was discounted. To clarify how myostatin deficiency affects the control of body fat mass and energy balance, we compared rates of oxygen consumption, body composition, and food intake in young myostatin-deficient mice relative to wild-type (WT) and heterozygous (HET) controls. We report that after adjusting for total body mass using regression analysis, young myostatin-deficient mice display significantly increased EE relative to both WT (+0.81 ± 0.28 kcal/day, P = 0.004) and HET controls (+0.92 ± 0.31 kcal/day, P = 0.005). Since food intake was not different between groups, increased EE likely accounts for the reduced body fat mass (KO: 8.8 ± 1.1% vs. WT: 14.5 ± 1.3%, P = 0.003) and circulating leptin levels (KO: 0.7 ± 0.2 ng/ml vs. WT: 1.9 ± 0.3 ng/ml, P = 0.008). Interestingly, the observed increase in adjusted EE in myostatin-deficient mice occurred despite dramatically reduced ambulatory activity levels (-50% vs. WT, P < 0.05). The absence of hyperphagia together with increased EE in myostatin-deficient mice suggests that increased leptin sensitivity may contribute to their lean phenotype. Indeed, leptin-induced anorexia (KO: -17 ± 1.2% vs. WT: -5 ± 0.3%) and weight loss (KO: -2.2 ± 0.2 g vs. WT: -1.6 ± 0.1, P < 0.05) were increased in myostatin-deficient mice compared with WT controls. We conclude that increased EE, together with increased leptin sensitivity, contributes to low fat mass in mice lacking myostatin.

Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia.

The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic ß-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.

Identification of a physiological role for leptin in the regulation of ambulatory activity and wheel running in mice.

Mechanisms regulating spontaneous physical activity remain poorly characterized despite evidence of influential genetic and acquired factors. We evaluated ambulatory activity and wheel running in leptin-deficient ob/ob mice and in wild-type mice rendered hypoleptinemic by fasting in both the presence and absence of subcutaneous leptin administration. In ob/ob mice, leptin treatment to plasma levels characteristic of wild-type mice acutely increased both ambulatory activity (by 4,000 ± 200 beam breaks/dark cycle, P < 0.05) and total energy expenditure (TEE; by 0.11 ± 0.01 kcal/h during the dark cycle, P < 0.05) in a dose-dependent manner and acutely increased wheel running (+350%, P < 0.05). Fasting potently increased ambulatory activity and wheel running in wild-type mice (AA: +25%, P < 0.05; wheel running: +80%, P < 0.05), and the effect of fasting was more pronounced in ob/ob mice (AA: +400%, P < 0.05; wheel running: +1,600%, P < 0.05). However, unlike what occurred in ad libitum-fed ob/ob mice, physiological leptin replacement attenuated or prevented fasting-induced increases of ambulatory activity and wheel running in both wild-type and ob/ob mice. Thus, plasma leptin is a physiological regulator of spontaneous physical activity, but the nature of leptin's effect on activity is dependent on food availability.

Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids.

Hypothalamic inflammation induced by high-fat feeding causes insulin and leptin resistance and contributes to the pathogenesis of obesity. Since in vitro exposure to saturated fatty acids causes inflammation and insulin resistance in many cultured cell types, we determined how cultured hypothalamic neurons respond to this stimulus. Two murine hypothalamic neuronal cell cultures, N43/5 and GT1-7, were exposed to escalating concentrations of saturated fatty acids for up to 24 h. Harvested cells were evaluated for activation of inflammation by gene expression and protein content. Insulin-treated cells were evaluated for induction of markers of insulin receptor signaling (p-IRS, p-Akt). In both hypothalamic cell lines, inflammation was induced by prototypical inflammatory mediators LPS and TNFalpha, as judged by induction of IkappaBalpha (3- to 5-fold) and IL-6 (3- to 7-fold) mRNA and p-IkappaBalpha protein, and TNFalpha pretreatment reduced insulin-mediated p-Akt activation by 30% (P < 0.05). By comparison, neither mixed saturated fatty acid (100, 250, or 500 microM for

Central administration of interleukin-4 exacerbates hypothalamic inflammation and weight gain during high-fat feeding.

In peripheral tissues, the link between obesity and insulin resistance involves low-grade inflammation induced by macrophage activation and proinflammatory cytokine signaling. Since proinflammatory cytokines are also induced in the hypothalamus of animals placed on a high-fat (HF) diet and can inhibit neuronal signal transduction pathways required for normal energy homeostasis, hypothalamic inflammation is hypothesized to contribute to the pathogenesis of diet-induced obesity (DIO). We addressed this hypothesis by perturbing the inflammatory milieu of the hypothalamus in adult male Wistar rats using intracerebroventricular (icv) administration of interleukin-4 (IL-4), a Th2 cytokine that promotes alternative activation (M2) of macrophages and microglia. During HF feeding, icv IL-4 administration increased hypothalamic proinflammatory cytokine gene expression and caused excess weight gain. Intracerebroventricular pretreatment with PS1145, an inhibitor of IKKbeta (a key intracellular mediator of inflammatory signaling), blocked both IL-4 effects, suggesting a causal relationship between IL-4-induced weight gain and hypothalamic inflammation. These observations add to growing evidence linking hypothalamic inflammation to obesity pathogenesis.