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This review discusses what we have learned about the neural regulation of feeding from genetic studies, both from studies in mutant mice and more recent genome-wide association studies in humans. Over the past 20 years, genetic studies have illuminated critical pathways in the hypothalamus and brainstem mediating energy homeostasis, such as the melanocortin, leptin, 5-hydroxytryptamine and brain-derived neurotrophic factor signaling axes. The identification of these pathways necessary for appropriate appetitive responses to energy state has yielded insight into normal homeostatic processes. Although monogenic alterations in each of these axes result in severe obesity, such cases remain rare. The major burden of disease is carried by those with common obesity, which has so far resisted yielding meaningful biological insights. Recent progress into the etiology of common obesity has been made with genome-wide association studies. Such studies now reveal more than 32 different candidate obesity genes, most of which are highly expressed or known to act in the CNS, emphasizing, as in rare monogenic forms of obesity, the role of the brain in predisposition to obesity.

The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCKNTS) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCKNTS neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4RPVH) cells, which are also responsive to CCK. Optogenetic activation of CCKNTS axon terminals within the PVH reveal the satiating function of CCKNTS neurons to be mediated by a CCKNTS→PVH pathway that also encodes positive valence. These data identify the functional significance of CCKNTS neurons and reveal a sufficient and discrete NTS to hypothalamus circuit controlling appetite. Obesity primarily results from eating more food than the body requires, the energy from which is then stored as fat. In recent years obesity has become increasingly common, with the resulting health problems presenting one of the major healthcare challenges of the twenty-first century. New ways to tackle the obesity epidemic are therefore required to improve human health on a global scale. To regulate how much food is eaten, the gut sends chemical messengers to the brain about how much food has been consumed. These messengers activate particular cells in the brain that signal to other brain regions to trigger a decision about whether we’ve had enough food to eat. This raises a question: if we can artificially activate these cells, can we ‘trick’ the brain into thinking that food has been consumed? A brain region called the nucleus of the solitary tract (NTS) is known to play a key role in receiving signals from the gut about meals. By studying mice, D’Agostino et al. found that cells in the NTS that make a brain hormone called cholecystokinin (CCK) are particularly activated by food. Further experiments then used a technique called optogenetics to activate these cells in mice that had free access to different types of food. This activation significantly reduced how hungry the mice were, causing them to eat less food and lose weight. D’Agostino et al. also showed that CCK cells relay the signal about food intake to a brain region called the hypothalamus. Overall, D’Agostino et al. have found a way to trick the brain into thinking that food has been eaten when it actually hasn’t, and for this reason mice eat less without feeling hungry and lose weight. The next step is to try and find a way to activate the CCK cells in obese humans who have health complications associated with excess body weight.

Obesity is primarily due to food intake in excess of the body's energetic requirements, intake that is not only associated with hunger but also the incentive value of food. The 5-hydroxytryptamine 2C receptor (5-HT2C R) is a target for the treatment of human obesity. Mechanistically, 5-HT2C Rs are positioned to influence both homeostatic feeding circuits within the hypothalamus and reward circuits within the ventral tegmental area (VTA). Here we investigated the role of 5-HT2C Rs in incentive motivation using a mathematical model of progressive ratio (PR) responding in mice. We found that the 5-HT2C R agonist lorcaserin significantly reduced both ad libitum chow intake and PR responding for chocolate pellets and increased c-fos expression in VTA 5-HT2C R expressing γ-aminobutyric acid (GABA) neurons, but not 5-HT2C R expressing dopamine (DA) neurons. We next adopted a chemogenetic approach using a 5-HT2C RCRE line to clarify the function of subset of 5-HT2C receptor expressing VTA neurons in the modulation of appetite and food-motivated behavior. Activation of VTA 5-HT2C receptor expressing neurons significantly reduced ad libitum chow intake, operant responding for chocolate pellets, and the incentive value of food. In contrast, chemogenetic inhibition of VTA 5-HT2C receptor expressing neurons had no effect on the feeding behavior. These results indicate that activation of the subpopulation of 5-HT2C R neurons within the VTA is sufficient to significantly reduce homeostatic feeding and effort-based intake of palatable food, and that this subset has an inhibitory role in motivational processes. These findings are relevant to the treatment of obesity.

The autonomic nervous system regulates fuel availability and energy storage in the liver, adipose tissue, and other organs; however, the molecular components of this neural circuit are poorly understood. We sought to identify neural populations that project from the CNS indirectly through multisynaptic pathways to liver and epididymal white fat in mice using pseudorabies virus strains expressing different reporters together with BAC transgenesis and immunohistochemistry. Neurons common to both circuits were identified in subpopulations of the paraventricular nucleus of the hypothalamus (PVH) by double labeling with markers expressed in viruses injected in both sites. The lateral hypothalamus and arcuate nucleus of the hypothalamus and brainstem regions (nucleus of the solitary tract and A5 region) also project to both tissues but are labeled at later times. Connections from these same sites to the PVH were evident after direct injection of virus into the PVH, suggesting that these regions lie upstream of the PVH in a common pathway to liver and adipose tissue (two metabolically active organs). These common populations of brainstem and hypothalamic neurons express neuropeptide Y and proopiomelanocortin in the arcuate nucleus, melanin-concentrating hormone, and orexin in the lateral hypothalamus and in the corticotrophin-releasing hormone and oxytocin in the PVH. The delineation of this circuitry will facilitate a functional analysis of the possible role of these potential command-like neurons to modulate autonomic outflow and coordinate metabolic responses in liver and adipose tissue.

Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents leptin resistance should promote weight normalisation and improve glucose homeostasis. The protease Bace1 drives beta amyloid (Aβ) production with obesity elevating hypothalamic Bace1 activity and Aβ 1–42 production. Pharmacological inhibition of Bace1 reduces body weight, improves glucose homeostasis and lowers plasma leptin in diet-induced obese (DIO) mice. These actions are not apparent in ob/ob or db/db mice, indicating the requirement for functional leptin signalling. Decreasing Bace1 activity normalises hypothalamic inflammation, lowers PTP1B and SOCS3 and restores hypothalamic leptin sensitivity and pSTAT3 response in obese mice, but does not affect leptin sensitivity in lean mice. Raising central Aβ 1–42 levels in the early stage of DIO increases hypothalamic basal pSTAT3 and reduces the amplitude of the leptin pSTAT3 signal without increased inflammation. Thus, elevated Aβ 1–42 promotes hypothalamic leptin resistance, which is associated with diminished whole-body sensitivity to exogenous leptin and exacerbated body weight gain in high fat fed mice. These results indicate that Bace1 inhibitors, currently in clinical trials for Alzheimer’s disease, may be useful agents for the treatment of obesity and associated diabetes.

Developmental programming links growth in early life with health status in adulthood. Although environmental factors such as maternal diet can influence the growth and adult health status of offspring, the genetic influences on this process are poorly understood. Using the mouse as a model, we identify the imprinted gene Grb10 as a mediator of nutrient supply and demand in the postnatal period. The combined actions of Grb10 expressed in the mother, controlling supply, and Grb10 expressed in the offspring, controlling demand, jointly regulate offspring growth. Furthermore, Grb10 determines the proportions of lean and fat tissue during development, thereby influencing energy homeostasis in the adult. Most strikingly, we show that the development of normal lean/fat proportions depends on the combined effects of Grb10 expressed in the mother, which has the greater effect on offspring adiposity, and Grb10 expressed in the offspring, which influences lean mass. These distinct functions of Grb10 in mother and pup act complementarily, which is consistent with a coadaptation model of imprinting evolution, a model predicted but for which there is limited experimental evidence. In addition, our findings identify Grb10 as a key genetic component of developmental programming, and highlight the need for a better understanding of mother-offspring interactions at the genetic level in predicting adult disease risk.

The neurotransmitter serotonin is an important regulator of energy balance. In the brain, serotonergic fibres from midbrain raphe nuclei project to key feeding centres, where serotonin acts on specific receptors to modulate the activity of various downstream neuropeptide systems and autonomic pathways and thus affects ingestive behaviour and energy expenditure. Serotonin, released by intestinal enterochromaffin cells, also appears to regulate energy homeostasis through peripheral mechanisms. Serotonergic effects on energy balance lead to secondary effects on glucose homeostasis, based on a well-established link between obesity and insulin resistance. However, serotonergic pathways may also directly affect glucose homeostasis through regulation of autonomic efferents and/or action on peripheral tissues. Several serotonergic compounds have been evaluated for clinical use in the treatment of obesity and type 2 diabetes; results of these trials are discussed here. Finally, future directions in the elucidation of serotonergic metabolic regulation are discussed.

As patients decline from health to type 2 diabetes, glucose-stimulated insulin secretion (GSIS) typically becomes impaired. Although GSIS is driven predominantly by direct sensing of a rise in blood glucose by pancreatic β-cells, there is growing evidence that hypothalamic neurons control other aspects of peripheral glucose metabolism. Here we investigated the role of the brain in the modulation of GSIS. To examine the effects of increasing or decreasing hypothalamic glucose sensing on glucose tolerance and insulin secretion, glucose or inhibitors of glucokinase, respectively, were infused into the third ventricle during intravenous glucose tolerance tests (IVGTTs). Glucose-infused rats displayed improved glucose handling, particularly within the first few minutes of the IVGTT, with a significantly lower area under the excursion curve within the first 10 min (AUC0-10). This was explained by increased insulin secretion. In contrast, infusion of the glucokinase inhibitors glucosamine or mannoheptulose worsened glucose tolerance and decreased GSIS in the first few minutes of IVGTT. Our data suggest a role for brain glucose sensors in the regulation of GSIS, particularly during the early phase. We propose that pharmacological agents targeting hypothalamic glucose-sensing pathways may represent novel therapeutic strategies for enhancing early phase insulin secretion in type 2 diabetes.

Aims Stanniocalcin‐2 (STC2) has recently been implicated in human muscle mass variability by genetic analysis. Biochemically, STC2 inhibits the proteolytic activity of the metalloproteinase PAPP‐A, which promotes muscle growth by upregulating the insulin‐like growth factor (IGF) axis. The aim was to examine if STC2 affects skeletal muscle mass and to assess how the IGF axis mediates muscle hypertrophy induced by functional overload. Methods We compared muscle mass and muscle fiber morphology between Stc2−/− (n = 21) and wild‐type (n = 15) mice. We then quantified IGF1, IGF2, IGF binding proteins −4 and −5 (IGFBP‐4, IGFBP‐5), PAPP‐A and STC2 in plantaris muscles of wild‐type mice subjected to 4‐week unilateral overload (n = 14). Results Stc2−/− mice showed up to 10% larger muscle mass compared with wild‐type mice. This increase was mediated by greater cross‐sectional area of muscle fibers. Overload increased plantaris mass and components of the IGF axis, including quantities of IGF1 (by 2.41‐fold, p = 0.0117), IGF2 (1.70‐fold, p = 0.0461), IGFBP‐4 (1.48‐fold, p = 0.0268), PAPP‐A (1.30‐fold, p = 0.0154) and STC2 (1.28‐fold, p = 0.019). Conclusion Here we provide evidence that STC2 is an inhibitor of muscle growth upregulated, along with other components of the IGF axis, during overload‐induced muscle hypertrophy.

D-fenfluramine (d-FEN) was once widely prescribed and was among the most effective weight loss drugs, but was withdrawn from clinical use because of reports of cardiac complications in a subset of patients. Discerning the neurobiology underlying the anorexic action of d-FEN may facilitate the development of new drugs to prevent and treat obesity. Through a combination of functional neuroanatomy, feeding, and electrophysiology studies in rodents, we show that d-FEN-induced anorexia requires activation of central nervous system melanocortin pathways. These results provide a mechanistic explanation of d-FEN's anorexic actions and indicate that drugs targeting these downstream melanocortin pathways may prove to be effective and more selective anti-obesity treatments.