Catherine B. Lawrence

Alternative role for prolactin-releasing peptide in the regulation of food intake.

Prolactin-releasing peptide (PrRP) is a peptide ligand for the human orphan G-protein-coupled receptor hGR3/GPR10 and causes the secretion of prolactin from anterior pituitary cells. However, the lack of immunoreactive staining for PrRP in the external layer of the median eminence seems to rule out this peptide as a classical hypophysiotropic hormone and, furthermore, PrRP is less effective than another inducer of prolactin secretion, thyrotropin-releasing hormone, both in vitro and in vivo. Here we show a reduction in the expression of PrRP mRNA during lactation and fasting and an acute effect of PrRP on food intake and body weight, supporting the hypothesis of an alternative role for the peptide.

Interleukin-1beta and the interleukin-1 receptor antagonist act in the striatum to modify excitotoxic brain damage in the rat.

The cytokine interleukin‐1 (IL‐1) has been implicated in ischaemic, traumatic and excitotoxic brain damage. The results presented here reveal novel actions of IL‐1 in the striatum which markedly exacerbate cortical neuronal damage elicited by local excitotoxins in the striatum or cortex.

Centrally administered galanin-like peptide modifies food intake in the rat: a comparison with galanin.

Galanin‐like peptide (GALP) is a recently identified neuropeptide that shares sequence homology with the orexigenic neuropeptide, galanin. In contrast to galanin, GALP is reported to bind preferentially to the galanin receptor 2 subtype (GalR2) compared to GalR1. The aim of this study was to determine the effect of GALP on feeding, body weight and core body temperature after central administration in rats compared to the effects of galanin. Intracerebroventricular (i.c.v.) injection of GALP (1 µg−10 µg) significantly stimulated feeding at 1 h in both satiated and fasted Sprague‐Dawley rats. However, 24 h after GALP injection, body weight gain was significantly reduced and food intake was also usually decreased. In addition, i.c.v. GALP caused a dose‐related increase in core body temperature, which lasted until 6–8 h after injection, and was reduced by peripheral administration of the cyclooxygenase inhibitor, flurbiprofen (1 mg/kg). Similar to GALP, i.c.v. injection of galanin (5 µg) significantly increased feeding at 1 h in satiated rats. However, there was no difference in food intake and body weight at 24 h, and galanin only caused a transient rise in body temperature. Thus, similar to galanin, GALP has an acute orexigenic effect on feeding. However, GALP also has an anorectic action, which is apparent at a later time. Therefore, GALP has complex opposing actions on energy homeostasis.

Anorexic but not pyrogenic actions of interleukin-1 are modulated by central melanocortin-3/4 receptors in the rat.

The cytokine interleukin‐1 (IL‐1), which mediates many responses to infection and injury, induces anorexia and fever through direct actions in the central nervous system. The melanocortin neuropeptides, such as alpha melanocyte‐stimulating hormone (α‐MSH), reportedly antagonize many actions of IL‐1, including fever and anorexia. However, it is unknown whether endogenous melanocortins modulate anorexia induced by IL‐1. The objective of the present study was to establish the effect of endogenous melanocortins on IL‐1‐induced anorexia and fever in the rat. Intracerebroventricular (i.c.v.) injection of IL‐1β caused a significant reduction in food intake and body weight gain, and a rise in core body temperature in conscious rats. Coadministration of the melanocortin‐3/4 receptor (MC3/4‐R) antagonist, SHU9119, reversed IL‐1β‐induced reductions in food intake and body weight, but did not affect the febrile response to IL‐1β. These data suggest IL‐1β may elicit its effects on food intake through the melanocortin system, predominantly via the MC3‐R or MC4‐R. In contrast, IL‐1β‐induced fever does not appear to be mediated or modulated by MC3‐R or MC4‐R activity.

High-fat diet-induced memory impairment in triple-transgenic Alzheimer's disease (3xTgAD) mice is independent of changes in amyloid and tau pathology.

Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimers disease (AD). Diets high in fat also increase disease neuropathology and/or cognitive deficits in AD mouse models. However, the effect of a high-fat diet on both the neuropathology and memory impairments in the triple-transgenic mouse model of AD (3xTgAD) is unknown. Therefore, groups of 2-month-old male 3xTgAD and control (non-Tg) mice were maintained on a high-fat or control diet and memory was assessed at the age of 3–4, 7–8, 11–12, and 15–16 months using a series of behavioral tests. A comparable increase in body weight was observed in non-Tg and 3xTgAD mice after high-fat feeding at all ages tested but a significantly greater increase in epididymal adipose tissue was observed in 3xTgAD mice at the age of 7–8, 11–12, and 15–16 months. A high-fat diet caused memory impairments in non-Tg control mice as early as the age of 3–4 months. In 3xTgAD mice, high-fat consumption led to a reduction in the age of onset and an increase in the extent of memory impairments. Some of these effects of high-fat diet on cognition in non-Tg and 3xTgAD mice were transient, and the age at which cognitive impairment was detected depended on the behavioral test. The effect of high-fat diet on memory in the 3xTgAD mice was independent of changes in AD neuropathology as no significant differences in (plaques, oligomers) or tau neuropathology were observed. An acute increase in microglial activation was seen in high-fat fed 3xTgAD mice at the age of 3–4 months but in non-Tg control mice microglial activation was not observed until the age of 15–16 months. These data indicate therefore that a high-fat diet has rapid and long-lasting negative effects on memory in both control and AD mice that are associated with neuroinflammation, but independent of changes in beta amyloid and tau neuropathology in the AD mice.

Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimers disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimers disease therapeutics.

Hypothalamic control of feeding.

Our understanding of the hypothalamic control of energy homeostasis has increased greatly since the discovery of leptin, the adipose cell derived protein. Recent studies have identified several new hypothalamic neuropeptides that affect food intake and energy balance. By studying these molecules and their neuronal systems, receptors and interactions, we are beginning to unravel the circuitry between peripheral adipogenic signals and hypothalamic effector pathways.

Obese mice exhibit an altered behavioural and inflammatory response to lipopolysaccharide.

SUMMARY Obesity is associated with an increase in the prevalence and severity of infections. Genetic animal models of obesity (ob/ob and db/db mice) display altered centrally-mediated sickness behaviour in response to acute inflammatory stimuli such as lipopolysaccharide (LPS). However, the effect of diet-induced obesity (DIO) on the anorectic and febrile response to LPS in mice is unknown. This study therefore determined how DIO and ob/ob mice respond to a systemic inflammatory challenge. C57BL/6 DIO and ob/ob mice, and their respective controls, were given an intraperitoneal (i.p.) injection of LPS. Compared with controls, DIO and ob/ob mice exhibited an altered febrile response to LPS (100 μg/kg) over 8 hours. LPS caused a greater and more prolonged anorexic effect in DIO compared with control mice and, in ob/ob mice, LPS induced a reduction in food intake and body weight earlier than it did in controls. These effects of LPS in obese mice were also seen after a fixed dose of LPS (5 μg). LPS (100 μg/kg) induced Fos protein expression in several brain nuclei of control mice, with fewer Fos-positive cells observed in the brains of obese mice. An altered inflammatory response to LPS was also observed in obese mice compared with controls: changes in cytokine expression and release were detected in the plasma, spleen, liver and peritoneal macrophages in obese mice. In summary, DIO and ob/ob mice displayed an altered behavioural response and cytokine release to systemic inflammatory challenge. These findings could help explain why obese humans show increased sensitivity to infections.

Increased brain microvascular MMP-9 and incidence of haemorrhagic transformation in obese mice after experimental stroke

Obesity is an independent risk factor for stroke and is associated with poorer outcome after stroke. We investigated whether this poorer outcome is related to brain microvascular disruption. Focal cerebral ischaemia was induced in lean or obese (ob/ob) mice by transient middle cerebral artery occlusion. The incidence of haemorrhagic transformation and the volume of ischaemic brain damage were significantly greater in obese mice. Blood–brain barrier permeability and brain microvascular MMP-9 expression were also markedly increased in obese mice. These effects were independent of leptin or glycaemic status, suggesting that obesity potentiates brain microvascular disruption after experimental stroke.

Anorectic brainstem peptides: more pieces to the puzzle.

Eating a meal is a mechanical process involving autonomous pathways that relay sensory and motor information between the whole length of the digestive tract and the central nervous system. This circuitry is able to initiate and terminate the meal, primarily by gut-brainstem-gut reflex arcs, and is independent of the caloric content of a meal. However, as part of our ability to regulate body weight over time, we must be able to modulate the amount of energy that we take in as food and the amount of energy that we expend. Thus, the gut-brainstem axis must be coupled to other systems that take account of factors such as food availability and preference, changing energy requirements and our social habits. Here, we review the importance of the brainstem nucleus of the tractus solitarius as a site of integration and the routes by which it connects the gut-brainstem axis with regulatory neuronal and endocrine networks that allow for strict body weight management.