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...

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.

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.