The dual hypothesis of homeostatic body weight regulation, including gravity-dependent and leptin-dependent actions.

Body weight is tightly regulated when outside the normal range. It has been proposed that there are individual-specific lower and upper intervention points for when the homeostatic regulation of body weight is initiated. The nature of the homeostatic mechanisms regulating body weight at the lower and upper ends of the body weight spectrum might differ. Previous studies demonstrate that leptin is the main regulator of body weight at the lower end of the body weight spectrum. We have proposed that land-living animals use gravity to regulate their body weight. We named this homeostatic system the gravitostat and proposed that there are two components of the gravitostat. First, an obvious mechanism involves increased energy consumption in relation to body weight when working against gravity on land. In addition, we propose that there exists a component, involving sensing of the body weight by osteocytes in the weight-bearing bones, resulting in a feedback regulation of energy metabolism and body weight. The gravity-dependent homeostatic regulation is mainly active in obese mice. We, herein, propose the dual hypothesis of body weight regulation, including gravity-dependent actions (= gravitostat) at the upper end and leptin-dependent actions at the lower end of the body weight spectrum. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.

Engagement of the brain orexin system in activity-based anorexia behaviour in mice.

While excessive physical activity is common amongst anorexia nervosa (AN) patients, contributing to their low body weight, little is known about the underlying biology and effective treatments targeting the hyperactivity are lacking. Given the role of orexin in arousal, physical activity and energy expenditure, we sought to investigate i) the extent to which orexin neurons are activated during severe anorectic state in the activity-based anorexia (ABA) mouse model, and ii) if the dual orexin receptor antagonist suvorexant can reduce physical activity during ABA. The Fos-TRAP2 technique enable us to visually capture active neurons (Fos expressing) during severe anorectic state in the ABA mouse model, and by immunohistochemistry, determine the extent to which these active neurons are orexin positive. In addition, suvorexant was administered peripherally to ABA mice and running activity was monitored. We found that a large population of orexin neurons in the hypothalamus are activated by ABA and that peripheral administration of suvorexant decreases food anticipatory activity in these mice. We conclude that orexin may be a suitable target to treat hyperactivity in AN and recommend further studies to examine the efficacy of suvorexant in aiding AN patients to control their drive for hyperactivity.

TRAPing Ghrelin-Activated Circuits: A Novel Tool to Identify, Target and Control Hormone-Responsive Populations in TRAP2 Mice.

The availability of Cre-based mouse lines for visualizing and targeting populations of hormone-sensitive cells has helped identify the neural circuitry driving hormone effects. However, these mice have limitations and may not even be available. For instance, the development of the first ghrelin receptor (Ghsr)-IRES-Cre model paved the way for using the Cre-lox system to identify and selectively manipulate ghrelin-responsive populations. The insertion of the IRES-Cre cassette, however, interfered with Ghsr expression, resulting in defective GHSR signaling and a pronounced phenotype in the homozygotes. As an alternative strategy to target ghrelin-responsive cells, we hereby utilize TRAP2 (targeted recombination in active populations) mice in which it is possible to gain genetic access to ghrelin-activated populations. In TRAP2 mice crossed with a reporter strain, we visualized ghrelin-activated cells and found, as expected, much activation in the arcuate nucleus (Arc). We then stimulated this population using a chemogenetic approach and found that this was sufficient to induce an orexigenic response of similar magnitude to that induced by peripheral ghrelin injection. The stimulation of this population also impacted food choice. Thus, the TRAPing of hormone-activated neurons (here exemplified by ghrelin-activated pathways) provides a complimentary/alternative technique to visualize, access and control discrete pathways, linking hormone action to circuit function.

A skeleton in the cupboard in ghrelin research: Where are the skinny dwarfs?

Based on studies delivering ghrelin or ghrelin receptor agonists, we have learned a great deal about the importance of the brain ghrelin signalling system for a wide range of physiological processes that include feeding behaviours, growth hormone secretion and glucose homeostasis. Because these processes can be considered as essential to life, the question arises as to why mouse models of depleted ghrelin signalling are not all skinny dwarfs with a host of behavioural and metabolic problems. Here, we provide a systematic detailed review of the phenotype of mice with deficient ghrelin signalling to help better understand the relevance and importance of the brain ghrelin signalling system, with a particular emphasis on those questions that remain unanswered.

A Body Weight Sensor Regulates Prepubertal Growth via the Somatotropic Axis in Male Rats.

In healthy conditions, prepubertal growth follows an individual specific growth channel. Growth hormone (GH) is undoubtedly the major regulator of growth. However, the homeostatic regulation to maintain the individual specific growth channel during growth is unclear. We recently hypothesized a body weight sensing homeostatic regulation of body weight during adulthood, the gravitostat. We now investigated if sensing of body weight also contributes to the strict homeostatic regulation to maintain the individual specific growth channel during prepubertal growth. To evaluate the effect of increased artificial loading on prepubertal growth, we implanted heavy (20% of body weight) or light (2% of the body weight) capsules into the abdomen of 26-day-old male rats. The body growth, as determined by change in biological body weight and growth of the long bones and the axial skeleton, was reduced in rats bearing a heavy load compared with light load. Removal of the increased load resulted in a catch-up growth and a normalization of body weight. Loading decreased hypothalamic growth hormone releasing hormone mRNA, liver insulin-like growth factor (IGF)-1 mRNA, and serum IGF-1, suggesting that the reduced body growth was caused by a negative feedback regulation on the somatotropic axis and this notion was supported by the fact that increased loading did not reduce body growth in GH-treated rats. Based on these data, we propose the gravitostat hypothesis for the regulation of prepubertal growth. This states that there is a homeostatic regulation to maintain the individual specific growth channel via body weight sensing, regulating the somatotropic axis and explaining catch-up growth.

Functional and Neurochemical Identification of Ghrelin Receptor (GHSR)-Expressing Cells of the Lateral Parabrachial Nucleus in Mice.

The lateral parabrachial nucleus (lPBN), located in the pons, is a well-recognized anorexigenic center harboring, amongst others, the calcitonin gene-related peptide (CGRP)-expressing neurons that play a key role. The receptor for the orexigenic hormone ghrelin (the growth hormone secretagogue receptor, GHSR) is also abundantly expressed in the lPBN and ghrelin delivery to this site has recently been shown to increase food intake and alter food choice. Here we sought to explore whether GHSR-expressing cells in the lPBN (GHSR lPBN cells) contribute to feeding control, food choice and body weight gain in mice offered an obesogenic diet, involving studies in which GHSR lPBN cells were silenced. We also explored the neurochemical identity of GHSR lPBN cells. To silence GHSR lPBN cells, Ghsr-IRES-Cre male mice were bilaterally injected intra-lPBN with a Cre-dependent viral vector expressing tetanus toxin-light chain. Unlike control wild-type littermates that significantly increased in body weight on the obesogenic diet (i.e., high-fat high-sugar free choice diet comprising chow, lard and 9% sucrose solution), the heterozygous mice with silenced GHSR lPBN cells were resistant to diet-induced weight gain with significantly lower food intake and fat weight. The lean phenotype appeared to result from a decreased food intake compared to controls and caloric efficiency was unaltered. Additionally, silencing the GHSR lPBN cells altered food choice, significantly reducing palatable food consumption. RNAscope and immunohistochemical studies of the lPBN revealed considerable co-expression of GHSR with glutamate and pituitary adenylate cyclase-activating peptide (PACAP), and much less with neurotensin, substance P and CGRP. Thus, the GHSR lPBN cells are important for diet-induced weight gain and adiposity, as well as in the regulation of food intake and food choice. Most GHSR lPBN cells were found to be glutamatergic and the majority (76%) do not belong to the well-characterized anorexigenic CGRP cell population.

Zona incerta neurons projecting to the ventral tegmental area promote action initiation towards feeding.

KEY POINTS: The zona incerta (ZI) and ventral tegmental area (VTA) are brain areas that are both implicated in feeding behaviour. The ZI projects to the VTA, although it has not yet been investigated whether this projection regulates feeding. We experimentally (in)activated the ZI to VTA projection by using dual viral vector technology, and studied the effects on feeding microstructure, the willingness to work for food, general activity and body temperature. Activity of the ZI to VTA projection promotes feeding by facilitating action initiation towards food, as reflected in meal frequency and the willingness to work for food reward, without affecting general activity or directly modulating body temperature. We show for the first time that activity of the ZI to VTA projection promotes feeding, which improves the understanding of the neurobiology of feeding behaviour and body weight regulation. ABSTRACT: Both the zona incerta (ZI) and the ventral tegmental area (VTA) have been implicated in feeding behaviour. The ZI provides prominent input to the VTA, although it has not yet been investigated whether this projection regulates feeding. Therefore, we investigated the role of ZI to VTA projection neurons in the regulation of several aspects of feeding behaviour. We determined the effects of (in)activation of ZI to VTA projection neurons on feeding microstructure, food-motivated behaviour under a progressive ratio schedule of reinforcement, locomotor activity and core body temperature. To activate or inactivate ZI neurons projecting to the VTA, we used a combination of canine adenovirus-2 in the VTA, as well as Cre-dependent designer receptors exclusively activated by designer drugs (DREADD) or tetanus toxin (TetTox) light chain in the ZI. TetTox-mediated inactivation of ZI to VTA projection neurons reduced food-motivated behaviour and feeding by reducing meal frequency. Conversely, DREADD-mediated chemogenetic activation of ZI to VTA projection neurons promoted food-motivated behaviour and feeding. (In)activation of ZI to VTA projection neurons did not affect locomotor activity or directly regulate core body temperature. Taken together, ZI neurons projecting to the VTA exert bidirectional control overfeeding behaviour. More specifically, activity of ZI to VTA projection neurons facilitate action initiation towards feeding, as reflected in both food-motivated behaviour and meal initiation, without affecting general activity.

Ghrelin Induces Place Preference for Social Interaction in the Larger Peer of a Male Rat Pair.

Social interaction is important for survival in most social species including humans. To ensure social activities, individuals experience reward from social interaction, generating a powerfully reinforcing process. Here we hypothesized that reward from social interaction in a juvenile male rat pair may be enhanced by ghrelin, a circulating hormone that has been shown to enhance reward from other natural (e.g. food, sex) as well as artificial reinforcers (e.g. alcohol and other drugs of abuse). To this end, we assessed the impact of ghrelin and a ghrelin antagonist on preference for a chamber previously paired to the presence of a social partner in a conditioned place preference paradigm. We found that ghrelin increased and a ghrelin antagonist decreased preference for social interaction, but only in the heavier partner in a social pair. In addition, we found that administered ghrelin induced a positive association between preference for social interaction and body weight difference within socially interacting pairs, where larger ghrelin treated rats preferred social interaction, whereas smaller ghrelin treated rats avoided it, which raises the question if ghrelin could have a role in implementing social hierarchies in rats. In summary, we conclude that ghrelin signaling increases the reward from social interaction in a manner that reflects the degree of divergence in body weight between the social pair.

Rats that are predisposed to excessive obesity show reduced (leptin-induced) thermoregulation even in the preobese state.

Both feeding behavior and thermogenesis are regulated by leptin. The sensitivity to leptin's anorexigenic effects on chow diet was previously shown to predict the development of diet-induced obesity. In this study, we determined whether the sensitivity to leptin's anorexigenic effects correlates with leptin's thermogenic response, and if this response is exerted at the level of the dorsomedial hypothalamus (DMH), a brain area that plays an important role in thermoregulation. Based on the feeding response to injected leptin on a chow diet, rats were divided into leptin-sensitive (LS) and leptin-resistant (LR) groups. The effects of leptin on core body, brown adipose tissue (BAT) and tail temperature were compared after intravenous versus intra-DMH leptin administration. After intravenous leptin injection, LS rats increased their BAT thermogenesis and reduced heat loss via the tail, resulting in a modest increase in core body temperature. The induction of these thermoregulatory mechanisms with intra-DMH leptin was smaller, but in the same direction as with intravenous leptin administration. In contrast, LR rats did not show any thermogenic response to either intravenous or intra-DMH leptin. These differences in the thermogenic response to leptin were associated with a 1°C lower BAT temperature and reduced UCP1 expression in LR rats under ad libitum feeding. The preexisting sensitivity to the anorexigenic effects of leptin, a predictor for obesity, correlates with the sensitivity to the thermoregulatory effects of leptin, which appears to be exerted, at least in part, at the level of the DMH.

Divergent Metabolic Effects of Acute Versus Chronic Repeated Forced Swim Stress in the Rat.

OBJECTIVE: This study sought to examine divergence regarding the impact of acute versus chronic repeated stress on energy balance. METHODS: Rats were exposed to either chronic repeated forced swim (FS) stress for 7 days or an acute stress (a single FS). Body weight and food intake were measured daily. Metabolic parameters explored included brown adipose tissue (BAT) weight and activity. RESULTS: Chronic repeated FS stress decreased body weight and caloric efficiency. It also increased the relative weight of BAT. The same stressor delivered only once did not alter adrenal or BAT weight, but it did increase the metabolic activity of BAT. In stress-naive rats, acute FS stress induced an anorexigenic response during the first day after the stressor that caused a reduction in body weight (that persisted for 4 days). By contrast, the chronic FS rats did not show an anorexigenic response after the final stressor, and there was no change in body weight during the following 4 days. CONCLUSIONS: Rats exposed to chronic repeated FS stress adapt to the stressor over time; they become less sensitive to its anorexigenic effects and its metabolic effects in BAT, adaptations that ultimately reduce sensitivity to the weight-lowering effects of an acute stressor.

Impact of Free-Choice Diets High in Fat and Different Sugars on Metabolic Outcome and Anxiety-Like Behavior in Rats.

OBJECTIVE: Rats were exposed to free-choice diets (fat plus one of two different sugar solutions, glucose or sucrose), and the metabolic consequences and impact on locomotor activity and anxiety-like behavior were explored. METHODS: For 3 weeks, 7-week-old male rats were offered either chow only or free-choice high-fat diets differing in their added sugar: no sugar, sucrose, or glucose. In a second experiment, after 2 weeks on the diets, rats were switched from high sucrose to high glucose for two additional weeks. Metabolic end points included body weight, food intake, food choice, glycemic control, metabolic hormones, fat pad weight, brown adipose tissue weight, and gene expression. Behavioral analysis included locomotor and anxiety-like activity in the open field and elevated plus maze. RESULTS: Both sugar diets enhanced adiposity and induced hyperphagia, favoring unhealthier dietary selection above that of the control diets (chow or free-choice high-fat with no sugar). Despite isocaloric intake in the sugar-containing diets, offering glucose instead of sucrose was associated with improved insulin sensitivity. The sugar-containing diets reduced activity (but with movements of increased velocity) and induced an anxiety-like phenotype. CONCLUSIONS: Although free-choice diets negatively impacted on metabolism and anxiety-like behavior, replacing sucrose with glucose improved insulin sensitivity and may therefore be better for health.

Activation of the rat hypothalamic supramammillary nucleus by food anticipation, food restriction or ghrelin administration.

The circulating orexigenic hormone ghrelin targets many brain areas involved in feeding control and signals via a dedicated receptor, the growth hormone secretagogue receptor 1A. One unexplored target area for ghrelin is the supramammillary nucleus (SuM), a hypothalamic area involved in motivation and reinforcement and also recently linked to metabolic control. Given that ghrelin binds to the SuM, we explored whether SuM cells respond to ghrelin and/or are activated when endogenous ghrelin levels are elevated. We found that peripheral ghrelin injection activates SuM cells in rats, reflected by an increase in the number of cells expressing c-Fos protein in this area, as welll as by the predominantly excitatory response of single SuM cells recorded in in vivo electrophysiological studies. Further c-Fos mapping studies reveal that this area is also activated in rats in situations when circulating ghrelin levels are known to be elevated: in food-restricted rats anticipating the consumption of food and in fed rats anticipating the consumption of an energy-dense food. We also show that intra-SuM injection of ghrelin induces a feeding response in rats suggesting that, if peripheral ghrelin is able to access the SuM, it may have direct effects on this brain region. Collectively, our data demonstrate that the SuM is activated when peripheral ghrelin levels are high, further supporting the emerging role for this brain area in metabolic and feeding control.

Interleukin-6 is important for regulation of core body temperature during long-term cold exposure in mice.

Interleukin-6 (IL6) is a cytokine important for inducing the fever response during infection and has been reported to uphold core body temperature during acute cold exposure. Recently it has also been indicated that IL6 in serum increases in cold-exposed mice. The aim of the present study was to investigate if IL6 is important for core body temperature regulation following a long-term cold exposure in mice. Experiments were performed with global IL6 deficient (-/-) mice, mice with conditional IL6 receptor α (IL6Rα) knockdown in the central nervous system (CNS; IL6RαNesCre) and appropriate wild-type (Wt) controls. All mice were placed in a cold environment (4°C) for 6 days. Core body temperature and oxygen consumption were measured by telemetry probes and indirect calorimetry at room temperature (20°C), and during the first and last day of cold exposure. Brain stem, hypothalamus and white and brown adipose tissues from the cold-exposed mice were subjected to gene expression analysis. After 6 days in 4°C, the IL6-/- mice exhibited significantly lower body temperature and oxygen consumption compared with Wt mice (P<0.05). The IL6RαNesCre mice also exhibited lower body temperature compared with WtNesCre controls during the last day of cold exposure (P<0.05). Furthermore, an increase in the mRNA level of brain-derived neurotrophic factor (Bdnf) was detected in the brain stem of both IL6-/- and IL6RαNesCre mice compared with the Wt groups (P<0.05). The finding that body temperature was decreased in IL6-/- and IL6RαNesCre mice indicates a decrease in thermogenesis in these animals. Bdnf has previously been indicated to increase body temperature and could in the present study be a mechanistic factor involved in counteracting the low body temperature in IL6-/- and IL6RαNesCre mice. These results suggest that IL6 is not only involved in body temperature regulation during infection, but also during long-term cold exposure, probably through mechanisms in the CNS.

The association of serum leptin levels with food addiction is moderated by weight status in adolescent psychiatric inpatients.

Leptin is essential for the control of energy homeostasis and eating behaviour. We investigated potential associations between serum leptin levels and food addiction in adolescent psychiatric inpatients (n = 228). The most frequent psychiatric diagnoses were mood disorders, anxiety disorders, and substance use disorders. More than three quarters of the study group suffered from more than one psychiatric disorder. Food addiction was assessed with the Yale Food Addiction Scale. Leptin was determined in serum. Analyses were conducted for the whole body weight range and for distinct weight categories to evaluate a potential impact of known nonlinearity between leptin levels and satiety due to leptin resistance in obese. A weak negative association between food addiction and leptin in normal weight patients (ß = -0.11, p = .022) was detected. In contrast, food addiction was associated with a significantly higher serum leptin (ß = 0.16. p = .038) in overweight patients. Food addiction in normal weight patients might be associated with restrained eating, previously shown to involve reduced leptin levels. The small positive association of food addiction with higher serum leptin in overweight patients might reflect leptin resistance and overeating.

Body weight homeostat that regulates fat mass independently of leptin in rats and mice.

Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat ("gravitostat") that regulates fat mass.

Central administration of ghrelin induces conditioned avoidance in rodents.

Feelings of hunger carry a negative-valence (emotion) signal that appears to be conveyed through agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus. The circulating hunger hormone, ghrelin, activates these neurons although it remains unclear whether it also carries a negative-valence signal. Given that ghrelin also activates pathways in the midbrain that are important for reward, it remains possible that ghrelin could act as a positive reinforcer and hence, carry a positive-valence signal. Here we used condition preference/avoidance tests to explore the reinforcing/aversive properties of ghrelin, delivered by intracerebroventricular (ICV) injection (2µg/injection once a day for 4 days). We found that ICV ghrelin produces conditioned avoidance, both in a conditioned place preference/avoidance test (CPP/CPA, in which the animals avoid a chamber previously paired to ghrelin injection) and in a conditioned flavor preference/avoidance test (CFP/CFA, in which the animals consume/avoid a taste previously paired to ghrelin injection). These effects of ghrelin to induce a CPA were observed when conditioning to ghrelin occurred in the absence or presence of food. We did not find evidence, however, that brain ghrelin delivery to rats induces malaise (in the pica test). Our data indicate that ICV ghrelin carries a negative-valence signal consistent with its role as a circulating hunger hormone and with its effects to activate AgRP neurones.

Preproglucagon neurons in the hindbrain have IL-6 receptor-α and show Ca2+ influx in response to IL-6.

Neuronal circuits in the hypothalamus and hindbrain are of importance for control of food intake, energy expenditure, and fat mass. We have recently shown that treatment with exendin-4 (Ex-4), an analog of the proglucagon-derived molecule glucagon-like peptide 1 (GLP-1), markedly increases mRNA expression of the cytokine interleukin-6 (IL-6) in the hypothalamus and hindbrain and that this increase partly mediates the suppression of food intake and body weight by Ex-4. Endogenous GLP-1 in the central nervous system (CNS) is produced by preproglucagon (PPG) neurons of the nucleus of the solitary tract (NTS) in the hindbrain. These neurons project to various parts of the brain, including the hypothalamus. Outside the brain, IL-6 stimulates GLP-1 secretion from the gut and pancreas. In this study, we aim to investigate whether IL-6 can affect GLP-1-producing PPG neurons in the nucleus of the solitary tract (NTS) in mouse hindbrain via the ligand binding part of the IL-6 receptor, IL-6 receptor-α (IL-6Rα). Using immunohistochemistry, we found that IL-6Rα was localized on PPG neurons of the NTS. Recordings of these neurons in GCaMP3/GLP-1 reporter mice showed that IL-6 enhances cytosolic Ca(2+) concentration in neurons capable of expressing PPG. We also show that the Ca(2+) increase originates from the extracellular space. Furthermore, we found that IL-6Rα was localized on cells in the caudal hindbrain expressing immunoreactive NeuN (a neuronal marker) or CNP:ase (an oligodendrocyte marker). In summary, IL-6Rα is present on PPG neurons in the NTS, and IL-6 can stimulate these cells by increasing influx of Ca(2+) to the cytosol from the extracellular space.

Centrally Administered Ghrelin Acutely Influences Food Choice in Rodents.

We sought to determine whether the orexigenic hormone, ghrelin, is involved in the intrinsic regulation of food choice in rats. Ghrelin would seem suited to serve such a role given that it signals hunger information from the stomach to brain areas important for feeding control, including the hypothalamus and reward system (e.g. ventral tegmental area, VTA). Thus, in rats offered a choice of palatable foods (sucrose pellets and lard) superimposed on regular chow for 2 weeks, we explored whether acute central delivery of ghrelin (intracerebroventricular (ICV) or intra-VTA) is able to redirect their dietary choice. The major unexpected finding is that, in rats with high baseline lard intake, acute ICV ghrelin injection increased their chow intake over 3-fold, relative to vehicle-injected controls, measured at both 3 hr and 6 hr after injection. Similar effects were observed when ghrelin was delivered to the VTA, thereby identifying the VTA as a likely contributing neurobiological substrate for these effects. We also explored food choice after an overnight fast, when endogenous ghrelin levels are elevated, and found similar effects of dietary choice to those described for ghrelin. These effects of fasting on food choice were suppressed in models of suppressed ghrelin signaling (i.e. peripheral injection of a ghrelin receptor antagonist to rats and ghrelin receptor (GHSR) knock-out mice), implicating a role for endogenous ghrelin in the changes in food choice that occur after an overnight fast. Thus, in line with its role as a gut-brain hunger hormone, ghrelin appears to be able to acutely alter food choice, with notable effects to promote "healthy" chow intake, and identify the VTA as a likely contributing neurobiological substrate for these effects.

Regulation of body fat mass by the gut microbiota: Possible mediation by the brain.

New insight suggests gut microbiota as a component in energy balance. However, the underlying mechanisms by which gut microbiota can impact metabolic regulation is unclear. A recent study from our lab shows, for the first time, a link between gut microbiota and energy balance circuitries in the hypothalamus and brainstem. In this article we will review this study further.

Dietary polyunsaturated fatty acids increase survival and decrease bacterial load during septic Staphylococcus aureus infection and improve neutrophil function in mice.

Severe infection, including sepsis, is an increasing clinical problem that causes prolonged morbidity and substantial mortality. At present, antibiotics are essentially the only pharmacological treatment for sepsis. The incidence of resistance to antibiotics is increasing; therefore, it is critical to find new therapies for sepsis. Staphylococcus aureus is a major cause of septic mortality. Neutrophils play an important role in the defense against bacterial infections. We have shown that a diet with high levels of dietary saturated fatty acids decreases survival in septic mice, but the mechanisms behind this remain elusive. The aim of the present study was to investigate how the differences in dietary fat composition affect survival and bacterial load after experimental septic infection and neutrophil function in uninfected mice. We found that, after S. aureus infection, mice fed a polyunsaturated high-fat diet (HFD-P) for 8 weeks had increased survival and decreased bacterial load during sepsis compared with mice fed a saturated high-fat diet (HFD-S), similar to mice fed a low-fat diet (LFD). Uninfected mice fed HFD-P had a higher frequency of neutrophils in bone marrow than mice fed HFD-S. In addition, mice fed HFD-P had a higher frequency of neutrophils recruited to the site of inflammation in response to peritoneal injection of thioglycolate than mice fed HFD-S. Differences between the proportion of dietary protein and carbohydrate did not affect septic survival at all. In conclusion, polyunsaturated dietary fat increased both survival and efficiency of bacterial clearance during septic S. aureus infection. Moreover, this diet increased the frequency and chemotaxis of neutrophils, key components of the immune response to S. aureus infections.