Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo11C-acetate and PET-CT scanning to show that colonic acetate crosses the blood–brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through 13C high-resolution magic-angle-spinning that 13C acetate from fermentation of 13C-labelled carbohydrate in the colon increases hypothalamic 13C acetate above baseline levels. Hypothalamic 13C acetate regionally increases the 13C labelling of the glutamate–glutamine and GABA neuroglial cycles, with hypothalamic 13C lactate reaching higher levels than the ‘remaining brain’. These observations suggest that acetate has a direct role in central appetite regulation.

Obesity has become a major global health problem. Recently, attention has focused on the benefits of fermentable carbohydrates on modulating metabolism. Here, we take a system approach to investigate the physiological effects of supplementation with oligofructose‐enriched inulin (In). We hypothesize that supplementation with this fermentable carbohydrate will not only lead to changes in body weight and composition, but also to modulation in neuronal activation in the hypothalamus. Male C57BL/6 mice were maintained on a normal chow diet (control) or a high fat (HF) diet supplemented with either oligofructose‐enriched In or corn starch (Cs) for 9 weeks. Compared to HF+Cs diet, In supplementation led to significant reduction in average daily weight gain (mean ± s.e.m.: 0.19 ± 0.01 g vs. 0.26 ± 0.02 g, P < 0.01), total body adiposity (24.9 ± 1.2% vs. 30.7 ± 1.4%, P < 0.01), and lowered liver fat content (11.7 ± 1.7% vs. 23.8 ± 3.4%, P < 0.01). Significant changes were also observed in fecal bacterial distribution, with increases in both Bifidobacteria and Lactobacillius and a significant increase in short chain fatty acids (SCFA). Using manganese‐enhanced MRI (MEMRI), we observed a significant increase in neuronal activation within the arcuate nucleus (ARC) of animals that received In supplementation compared to those fed HF+Cs diet. In conclusion, we have demonstrated for the first time, in the same animal, a wide range of beneficial metabolic effects following supplementation of a HF diet with oligofructose‐enriched In, as well as significant changes in hypothalamic neuronal activity.

Kisspeptin (encoded by KISS1) is a crucial activator of reproductive function. The role of kisspeptin has been studied extensively within the hypothalamus but little is known about its significance in other areas of the brain. KISS1 and its cognate receptor are expressed in the amygdala, a key limbic brain structure with inhibitory projections to hypothalamic centers involved in gonadotropin secretion. We therefore hypothesized that kisspeptin has effects on neuronal activation and reproductive pathways beyond the hypothalamus and particularly within the amygdala. To test this, we mapped brain neuronal activity (using manganese-enhanced MRI) associated with peripheral kisspeptin administration in rodents. We also investigated functional relevance by measuring the gonadotropin response to direct intra-medial amygdala (MeA) administration of kisspeptin and kisspeptin antagonist. Peripheral kisspeptin administration resulted in a marked decrease in signal intensity in the amygdala compared to vehicle alone. This was associated with an increase in luteinizing hormone (LH) secretion. In addition, intra-MeA administration of kisspeptin resulted in increased LH secretion, while blocking endogenous kisspeptin signaling within the amygdala by administering intra-MeA kisspeptin antagonist decreased both LH secretion and LH pulse frequency. We provide evidence for the first time that neuronal activity within the amygdala is decreased by peripheral kisspeptin administration and that kisspeptin signaling within the amygdala contributes to the modulation of gonadotropin release and pulsatility. Our data suggest that kisspeptin is a ‘master regulator’ of reproductive physiology, integrating limbic circuits with the regulation of gonadotropin-releasing hormone neurons and reproductive hormone secretion.

There is an increased interest in investigating the relationship between the gut microbiota and energy homeostasis. Probiotics are health beneficial microbes mainly categorised under the genusLactobacillusandBifidobacterium, which when administered in adequate amounts confer health benefits to the host, and have been implicated in various physiological functions. The potential role of probiotics in energy homeostasis is a current and an emerging area of research. In the present study,Lactobacillus acidophilusNCDC 13 was used to evaluate its anti-obesity potential in diet-induced obese (C57BL/6) mice. The probiotic bacterial culture was administered in Indian yogurt preparation called ‘dahi’, prepared using native starter cultures, and compared with control dahi containing only dahi starter cultures. The dietary intervention was followed for 8 weeks, and whole-body fat composition, and liver and muscle adiposity were measured using MRI. Changes in gut microbiota were assessed by fluorescentin situhybridisation in faeces and caecal contents. The feeding of the probiotic brought no changes in body-weight gain, food and dahi intake when compared with the control dahi-fed animals. No significant changes in body fat composition, liver and muscle adiposity were also observed. At the end of the dietary intervention, a significant increase (P < 0·05) in the number of totalBifidobacteriumwas observed in both faeces and caecal contents of mice as a result of probiotic dahi administration. Thus,L. acidophilusNCDC 13 supplementation could be beneficial in shifting the gut microbiota balance positively. However, its anti-obesity potential could not be established in the present study and warrants further exploration.

BackgroundObesity is rising at an alarming rate globally. Different fermentable carbohydrates have been shown to reduce obesity. The aim of the present study was to investigate if two different fermentable carbohydrates (inulin and β-glucan) exert similar effects on body composition and central appetite regulation in high fat fed mice.Methodology/Principal FindingsThirty six C57BL/6 male mice were randomized and maintained for 8 weeks on a high fat diet containing 0% (w/w) fermentable carbohydrate, 10% (w/w) inulin or 10% (w/w) β-glucan individually. Fecal and cecal microbial changes were measured using fluorescent in situ hybridization, fecal metabolic profiling was obtained by proton nuclear magnetic resonance (1H NMR), colonic short chain fatty acids were measured by gas chromatography, body composition and hypothalamic neuronal activation were measured using magnetic resonance imaging (MRI) and manganese enhanced MRI (MEMRI), respectively, PYY (peptide YY) concentration was determined by radioimmunoassay, adipocyte cell size and number were also measured. Both inulin and β-glucan fed groups revealed significantly lower cumulative body weight gain compared with high fat controls. Energy intake was significantly lower in β-glucan than inulin fed mice, with the latter having the greatest effect on total adipose tissue content. Both groups also showed an increase in the numbers of Bifidobacterium and Lactobacillus-Enterococcus in cecal contents as well as feces. β- glucan appeared to have marked effects on suppressing MEMRI associated neuronal signals in the arcuate nucleus, ventromedial hypothalamus, paraventricular nucleus, periventricular nucleus and the nucleus of the tractus solitarius, suggesting a satiated state.Conclusions/SignificanceAlthough both fermentable carbohydrates are protective against increased body weight gain, the lower body fat content induced by inulin may be metabolically advantageous. β-glucan appears to suppress neuronal activity in the hypothalamic appetite centers. Differential effects of fermentable carbohydrates open new possibilities for nutritionally targeting appetite regulation and body composition.

Obesity is a pandemic syndrome frequently associated with the most prevalent pathologies in developed countries, including diabetes, atherosclerosis, ischemic episodes, and cancer (1). Obesity results from an imbalance in the complex system of peripheral and intrahypothalamic pathways controlling appetite regulation and energy homeostasis (2). The hypothalamic control of energy homeostasis involves interaction between food intake stimulating neurons (orexigenic), expressing neuropeptide Y/agouti-related protein (NPY/AGRP), and food intake inhibiting neurons (anorexigenic), expressing pro-opiomelanocortin/cocaine and amphetamine-regulated transcript (POMC/CART) (3,4). Peripheral signals have been shown to modulate the activity of NPY/AGRP and POMC neurons within key appetite regulating nuclei of the hypothalamus, such as the arcuate. These circulating factors include the well-known orexigenic peptide ghrelin, released from the oxyntic cells in the stomach, and the anorexigenic hormones insulin and leptin, released by the pancreas and the fat tissue (5,6). Despite the accumulated knowledge on neuropeptide signaling in the hypothalamus (2,3), little information is available on the integrated mechanism of neuronal activation during appetite regulation and how this circumstance could affect the neuroglial metabolic coupling mechanisms underlying neurotransmission events. On these grounds, methods providing further insight into hypothalamic metabolism and its disturbances entail considerable interest to improve our understanding, prognosis, and therapy of energy homeostasis and food intake disorders.In vivo and in vitro 1 H and 13 C NMR approaches have been successful in providing a wealth of information on cerebral metabolism and neuroglial interactions during sensory or motor activation (7-10). However, the relatively large voxel sizes involved in the acquisition of in vivo NMR spectra preclude its use in studying the relatively small hypothalamic area, particularly in small rodents. Similarly, the relatively large amounts of cerebral tissue needed to prepare brain extracts for high-resolution 13 C NMR constitute an important limitation for regional studies of hypothalamic processes. Recently, high-resolution magic angle spinning (HR-MAS) spectroscopy has been proposed as a convenient alternative (11). In this technique, the removal of dipolar couplings at the magic angle (54.7°) permits the acquisition of high-resolution spectra from small tissue samples, with similar quality to that only previously achievable via solution spectroscopy. In most cases, 1 H HR-MAS has been used for metabolic profiling of normal and diseased tissues (11), whereas 13 C HR-MAS offers the additional advantage of providing information on the operation of cerebral metabolic pathways and neuroglial coupling mechanisms, under similar conditions to high-resolution 13 C NMR spectroscopy (12) but using smaller tissue biopsies and without the need of solvent extraction. This makes it possible to investigate the oxida-

SummaryThe obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRβ) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TRβ in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TRβ in the VMH as a major physiological regulator of food intake and energy homeostasis.

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