The gut microbiota interacts with the host via neuroimmune, neuroendocrine and neural pathways. These pathways are components of the brain-gut-microbiota axis and preclinical evidence suggests that the microbiota can recruit this bidirectional communication system to modulate brain development, function and behaviour. The pathophysiology of depression involves neuroimmune-neuroendocrine dysregulation. However, the extent to which changes in gut microbiota composition and function mediate the dysregulation of these pathways is unknown. Thirty four patients with major depression and 33 matched healthy controls were recruited. Cytokines, CRP, Salivary Cortisol and plasma Lipopolysaccharide binding protein were determined by ELISA. Plasma tryptophan and kynurenine were determined by HPLC. Fecal samples were collected for 16s rRNA sequencing. A Fecal Microbiota transplantation was prepared from a sub group of depressed patients and controls and transferred by oral gavage to a microbiota-deficient rat model. We demonstrate that depression is associated with decreased gut microbiota richness and diversity. Fecal microbiota transplantation from depressed patients to microbiota-depleted rats can induce behavioural and physiological features characteristic of depression in the recipient animals, including anhedonia and anxiety-like behaviours, as well as alterations in tryptophan metabolism. This suggests that the gut microbiota may play a causal role in the development of features of depression and may provide a tractable target in the treatment and prevention of this disorder.

Hypothalamic fatty acid metabolism has recently been implicated in the controls of food intake and energy homeostasis. We report that intracerebroventricular (ICV) injection of leptin, concomitant with inhibiting AMP-activated kinase (AMPK), activates acetyl-CoA carboxylase (ACC), the key regulatory enzyme in fatty acid biosynthesis, in the arcuate nucleus (Arc) and paraventricular nucleus (PVN) in the hypothalamus. Arc overexpression of constitutively active AMPK prevents the Arc ACC activation in response to ICV leptin, supporting the hypothesis that AMPK lies upstream of ACC in leptin's Arc intracellular signaling pathway. Inhibiting hypothalamic ACC with 5-tetradecyloxy-2-furoic acid, a specific ACC inhibitor, blocks leptin-mediated decreases in food intake, body weight, and mRNA level of the orexigenic neuropeptide NPY. These results show that hypothalamic ACC activation makes an important contribution to leptin's anorectic effects. Furthermore, we find that ICV leptin up-regulates the level of malonyl-CoA (the intermediate of fatty acid biosynthesis) specifically in the Arc and increases the level of palmitoyl-CoA (a major product of fatty acid biosynthesis) specifically in the PVN. The rises of both levels are blocked by 5-tetradecyloxy-2-furoic acid along with the blockade of leptinmediated hypophagia. These data suggest malonyl-CoA as a downstream mediator of ACC in leptin's signaling pathway in the Arc and imply that palmitoyl-CoA, instead of malonyl-CoA, could be an effector in relaying ACC signaling in the PVN. Together, these findings highlight site-specific impacts of hypothalamic ACC activation in leptin's anorectic signaling cascade.carnitine palmitoyltransferase ͉ long-chain fatty acyl CoA ͉ malonyl CoA ͉ oleic acid ͉ malonyl CoA decarboxylase E nergy balance is maintained by hypothalamic systems responding to hormonal and neural signals that sense body energy status (1). Leptin is an anorexigenic hormone secreted mainly from adipocytes that controls food intake and energy homeostasis primarily by acting at hypothalamic nuclei such as the arcuate nucleus (Arc) (1, 2). The Arc, the primary nucleus in the hypothalamus in mediating leptin's control of energy balance, contains first-order neurons that express leptin receptors and a variety of feeding-related neuropeptides such as neuropeptide Y (NPY), agouti-related peptide (AgRP), and ␣-melanocyte stimulating hormone (␣-MSH) (1). Leptin exerts its anorectic effects by modulating the levels of these neuropeptides. Activation of signal transducer and activator of transcription 3 (STAT3) and activation of phosphatidylinositol 3-kinase have been shown to play critical roles in leptin's hypothalamic intracellular signaling pathways (3, 4).Further aspects of leptin's hypothalamic intracellular signaling have been identified. Minokoshi et al. (5) have demonstrated that exogenous administration of leptin inhibits AMP-activated kinase (AMPK) in the Arc, and, based on the finding that constitutive activity of AMPK in the Arc prevents leptin's anorectic acti...

Previous studies have suggested that neuropeptide Y (NPY) in the dorsomedial hypothalamus (DMH) serves as an important signaling peptide in the regulation of energy balance. To elucidate such actions, we used the adenoassociated virus (AAV) system to alter Npy gene expression in the DMH and examined the effects of these alterations on food intake and energy balance as well as explored its downstream signaling pathway. We found that AAV-mediated overexpression of NPY in the DMH of lean rats increased food intake and body weight, and exacerbated high-fat diet-induced obesity. Knockdown of NPY expression in the DMH via AAV-mediated RNA interference ameliorated the hyperphagia, obesity, and diabetes of Otsuka Long-Evans Tokushima Fatty (OLETF) rats. NPY knockdown in the DMH produced a nocturnal and meal size-specific feeding effect. Moreover, we found that knockdown of DMH NPY expression in intact rats reduced NPY content in the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus and affected within-meal satiation. DMH NPY knockdown increased the feeding inhibitory and NTS c-Fos responses to peripheral administration of cholecystokinin. Together, these results indicate that DMH NPY plays an important role in modulating food intake and energy balance and its dysregulation causes disordered energy balance leading to obesity.

The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which respectively define the peripheral and central GLP-1 systems. PPG neurons in the nucleus tractus solitarii (NTS) are widely assumed to link the peripheral and central GLP-1 systems in a unified gut-brain satiation circuit. However, direct evidence for this hypothesis is lacking, and the necessary circuitry remains to be demonstrated. Here we show that PPG NTS neurons encode satiation in mice, consistent with vagal signalling of gastrointestinal distension. However, PPG NTS neurons predominantly receive vagal input from oxytocin receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. PPG NTS neurons are not necessary for eating suppression by GLP-1 receptor agonists, and concurrent PPG NTS neuron activation suppresses eating more potently than semaglutide alone. We conclude that central and peripheral GLP-1 systems suppress eating via independent gut-brain circuits, providing a rationale for pharmacological activation of PPG NTS neurons in combination with GLP-1 receptor agonists as an obesity treatment strategy.

Otsuka Long-Evans Tokushima fatty (OLETF) rats lacking cholecystokinin-A receptors are hyperphagic, obese, and diabetic. Although exercise attenuates OLETF rats' obesity, the mechanisms underlying the effects of exercise are unclear. In this study, we determined the effects of running wheel activity on patterns of body weight gain, food intake, and hypothalamic gene expression. We demonstrate that voluntary running activity beginning at 8 wk of age normalized meal patterns, food intake, body weight, and plasma levels of glucose and leptin in OLETF rats. During the initial exercise period, corticotropin-releasing factor (CRF) mRNA expression was significantly elevated in the dorsomedial hypothalamus (DMH) but not in the paraventricular nucleus in both OLETF and control Long-Evans Tokushima rats. In response to long-term exercise, arcuate nucleus (Arc) neuropeptide Y (NPY), and proopiomelanocortin as well as DMH NPY and CRF mRNA expression were increased in Long-Evans Tokushima rats. In contrast, whereas exercising OLETF rats had increased Arc NPY and DMH CRF expression, Arc proopiomelanocortin and DMH NPY mRNA levels were not elevated. Finally, we demonstrate that the effects of exercise on body weight in OLETF rats were long lasting. Although food intake and body weight were increased in OLETF rats when running wheels were locked, weights did not return to those of sedentary OLETF rats. Together, these data suggest that the elevation of DMH CRF expression may mediate the short-term feeding inhibitory effects of exercise and that exercise limits the elevation of DMH NPY expression to account for the overall prevention of OLETF rats' obesity.

The prevalence of overweight and obesity has markedly increased during the past few decades. Stress has been suggested as one environmental factor that may contribute to the development of obesity. In this review, we discuss the role that exposure to chronic stress may play in the development of obesity, with particular attention to the effects of chronic psychosocial stress. Of particular importance is the effect that social stress has on dietary preference, food consumption, and regional distribution of adipose tissue. We present evidence from human and animal studies that links sympathetic nervous system and hypothalamic-pituitary-adrenal axis hyperactivity with visceral obesity, and that stress tends to alter the pattern of food consumption, and promotes craving of nutrient-dense “comfort foods.” Lastly, we discuss the visible burrow system, a model of chronic social stress used in our laboratory to assess the effects of social subordination on behavioral and metabolic profile.

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Although cholecystokinin A (CCK-A) receptors (CCK-AR) mediate the feeding inhibitory actions of CCK in both rats and mice, the absence of CCK-AR results in species-specific phenotypes. The lack of CCK-AR in Otsuka Long-Evans Tokushima fatty (OLETF) rats results in hyperphagia and obesity. We have suggested that demonstrated increases in meal size and elevated levels of dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) gene expression may contribute to this phenotype. In contrast to OLETF rats, CCK-AR(-/-) mice have normal total daily food intake and do not develop obesity. To assess the basis underlying the different phenotypes in rats and mice lacking CCK-AR, we characterized meal patterns in CCK-AR(-/-) mice and determined whether CCK-AR(-/-) mice exhibited an alteration in DMH NPY gene expression. We demonstrate that although CCK-AR(-/-) mice show a similar dysregulation in meal size as OLETF rats, they do not have an elevation in DMH NPY mRNA expression levels. In fact, intact mice have no CCK-AR in the DMH. Furthermore, in intact rats, NPY and CCK-AR are colocalized in DMH neurons, and parenchymal injection of CCK into the DMH reduces food intake and down-regulates DMH NPY mRNA expression. These results suggest that although CCK-AR plays a role in the mediation of CCK actions in the control of meal size in both rats and mice, CCK-AR seems to contribute to modulating DMH NPY levels only in rats. The deficit in CCK's action in the control of DMH NPY gene expression may play a major role in the obese phenotype in OLETF rats.