Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as ...early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation.
Hypothalamic RIP-expressing neurons regulate energy balance, but the precise neural pathways and neurotransmitters mediating this effect remain undetermined. Kong et al. (2012) now demonstrate that ...RIP neurons regulate energy expenditure and BAT thermogenesis predominantly via a GABAergic arcuate-paraventricular-hindbrain pathway.
The arcuate nucleus of the hypothalamus (ARH) is a key component of hypothalamic pathways regulating energy balance, and leptin is required for normal development of ARH projections. Diet-induced ...obesity (DIO) has a polygenic mode of inheritance, and DIO individuals develop the metabolic syndrome when a moderate amount of fat is added to the diet. Here we demonstrate that rats selectively bred to develop DIO, which are known to be leptin resistant before they become obese, have defective ARH projections that persist into adulthood. Furthermore, the ability of leptin to activate intracellular signaling in ARH neurons in vivo and to promote ARH neurite outgrowth in vitro is significantly reduced in DIO neonates. Thus, animals that are genetically predisposed toward obesity display an abnormal organization of hypothalamic pathways involved in energy homeostasis that may be the result of diminished responsiveness of ARH neurons to the trophic actions of leptin during postnatal development.
Sugar-sweetened beverage consumption is a known independent risk factor for nonalcoholic steatohepatitis (NASH). Non-caloric sweeteners (NCS) are food additives providing sweetness without calories ...and are considered safe and/or not metabolized by the liver. The potential role of newer NCS in the regulation of NASH, however, remain unknown. Our study aimed to determine the impact of newer NCS including Rebaudioside A and sucralose on NASH using high fat diet induced obesity mouse model by substituting fructose and sucrose with NCS in the drinking water. We characterized the phenotype of NCS- treated obesity and investigated the alterations of hepatic function and underlying mechanisms. We found that NCS have no impact on weight gain and energy balance in high fat diet induced obesity. However, in comparison to fructose and sucrose, Rebaudioside A significantly improved liver enzymes, hepatic steatosis and hepatic fibrosis. Additionally, Rebaudioside A improved endoplasmic reticulum (ER) stress related gene expressions, fasting glucose levels, insulin sensitivity and restored pancreatic islet cell mass, neuronal innervation and microbiome composition. We concluded that Rebaudioside A significantly ameliorated murine NASH, while the underlying mechanisms requires further investigation.
The prevalence of obesity and type 2 diabetes is growing at an alarming rate, including among pregnant women. Low-calorie sweeteners (LCSs) have increasingly been used as an alternative to sugar to ...deliver a sweet taste without the excessive caloric load. However, there is little evidence regarding their biological effects, particularly during development. Here, we used a mouse model of maternal LCS consumption to explore the impact of perinatal LCS exposure on the development of neural systems involved in metabolic regulation. We report that adult male, but not female, offspring from both aspartame- and rebaudioside A-exposed dams displayed increased adiposity and developed glucose intolerance. Moreover, maternal LCS consumption reorganized hypothalamic melanocortin circuits and disrupted parasympathetic innervation of pancreatic islets in male offspring. We then identified phenylacetylglycine (PAG) as a unique metabolite that was upregulated in the milk of LCS-fed dams and the serum of their pups. Furthermore, maternal PAG treatment recapitulated some of the key metabolic and neurodevelopmental abnormalities associated with maternal LCS consumption. Together, our data indicate that maternal LCS consumption has enduring consequences on the offspring's metabolism and neural development and that these effects are likely to be mediated through the gut microbial co-metabolite PAG.
Regulation of attention and promotion of behavioural flexibility are functions attributed to both the noradrenergic nucleus locus coeruleus (LC) and the prefrontal cortex (PFC). The PFC receives a ...large innervation from LC and small changes in catecholaminergic activity in PFC profoundly affect cognitive function. It is crucial to the understanding of learning‐related plasticity, that the cognitive context driving LC neurons be determined and the relation to activity in PFC be elucidated. To this end simultaneous recordings were made from LC and prelimbic cortex (PL) during an odour‐reward association task in the rat. Neuronal activity related to orientation of attention, reward predictability, reward itself, and changes in stimulus reinforcement contingencies, was measured. All LC neurons and a significant proportion of PL neurons were engaged during several aspects of a Go/NoGo task, especially after the signal for trial onset and CS+ presentation. LC activation was, however, more tightly aligned to the behavioural response than to the CS+ 22% of PL neurons were activated during the response‐reward delay. This suggests that the activity of both these structures is related to reward anticipation. Finally, LC neurons exhibited rapid plasticity when the reward‐contingency was modified. Within‐trial response latencies were always shorter in LC than in PL and between‐trial response adaptation in LC preceded that in PL by many trials. Identifying such temporal relationships is an essential step toward understanding how neuromodulatory inputs to forebrain networks might promote or permit experience‐dependent plasticity in behavioural situations.
Developmental effects of ghrelin Steculorum, Sophie M.; Bouret, Sebastien G.
Peptides (New York, N.Y. : 1980),
11/2011, Volume:
32, Issue:
11
Journal Article
Peer reviewed
Open access
• Ghrelin and GHSRs are expressed in the developing embryo and fetus. • Ghrelin influences perinatal growth. • Alterations in perinatal ghrelin levels cause structural differences in the pancreas, ...gastrointestinal tract, and brain.
Ghrelin is a pleiotropic hormone that was originally described as promoting feeding and stimulating growth hormone release in adults. A growing body of evidence suggests that ghrelin may also exert developmental and organizational effects during perinatal life. The perinatal actions of ghrelin include the regulation of early developmental events such as blastocyst development and perinatal growth. Moreover, alterations in perinatal ghrelin levels result in structural differences in various peripheral organs, such as the pancreas and gastrointestinal tract. Recent data have also suggested that ghrelin acts on appetite-related brain centers in early life. Together, these observations indicate that exposure to factors that alter how ghrelin impacts development may induce lasting effects on physiological regulation.
Summary Epidemiological studies suggest that emotional liability in infancy could be a predictor of anxiety-related disorders in the adulthood. Rats exposed to prenatal restraint stress (“PRS rats”) ...represent a valuable model for the study of the interplay between environmental triggers and neurodevelopment in the pathogenesis of anxious/depressive like behaviours. Repeated episodes of restraint stress were delivered to female Sprague-Dawley rats during pregnancy and male offspring were studied. Ultrasonic vocalization (USV) was assessed in pups under different behavioural paradigms. After weaning, anxiety was measured by conventional tests. Expression of GABAA receptor subunits and metabotropic glutamate (mGlu) receptors was assessed by immunoblotting. Plasma leptin levels were measured using a LINCOplex bead assay kit. The offspring of stressed dams emitted more USVs in response to isolation from their mothers and showed a later suppression of USV production when exposed to an unfamiliar male odour, indicating a pronounced anxiety-like profile. Anxiety like behaviour in PRS pups persisted one day after weaning. PRS pups did not show the plasma peak in leptin levels that is otherwise seen at PND14. In addition, PRS pups showed a reduced expression of the γ2 subunit of GABAA receptors in the amygdala at PND14 and PND22, an increased expression of mGlu5 receptors in the amygdala at PND22, a reduced expression of mGlu5 receptors in the hippocampus at PND14 and PND22, and a reduced expression of mGlu2/3 receptors in the hippocampus at PND22. These data offer a clear-cut demonstration that the early programming triggered by PRS could be already translated into anxiety-like behaviour during early postnatal life.
How does the noradrenergic nucleus locus coeruleus act on target networks to regulate behavior? In this issue of Neuron, Zerbi et al. (2019) combine functional neuroimaging and pharmacogenetics in ...mice to tackle that question, uncovering a network action underlying stress. And providing insight for cognition?
How does the noradrenergic nucleus locus coeruleus act on target networks to regulate behavior? In this issue of Neuron, Zerbi et al. (2019) combine functional neuroimaging and pharmacogenetics in mice to tackle that question, uncovering a network action underlying stress. And providing insight for cognition?
Humans have been shown to strategically explore. They can identify situations in which gathering information about distant and uncertain options is beneficial for the future. Because primates rely on ...scarce resources when they forage, they are also thought to strategically explore, but whether they use the same strategies as humans and the neural bases of strategic exploration in monkeys are largely unknown. We designed a sequential choice task to investigate whether monkeys mobilize strategic exploration based on whether information can improve subsequent choice, but also to ask the novel question about whether monkeys adjust their exploratory choices based on the contingency between choice and information, by sometimes providing the counterfactual feedback about the unchosen option. We show that monkeys decreased their reliance on expected value when exploration could be beneficial, but this was not mediated by changes in the effect of uncertainty on choices. We found strategic exploratory signals in anterior and mid-cingulate cortex (ACC/MCC) and dorsolateral prefrontal cortex (dlPFC). This network was most active when a low value option was chosen, which suggests a role in counteracting expected value signals, when exploration away from value should to be considered. Such strategic exploration was abolished when the counterfactual feedback was available. Learning from counterfactual outcome was associated with the recruitment of a different circuit centered on the medial orbitofrontal cortex (OFC), where we showed that monkeys represent chosen and unchosen reward prediction errors. Overall, our study shows how ACC/MCC-dlPFC and OFC circuits together could support exploitation of available information to the fullest and drive behavior towards finding more information through exploration when it is beneficial.
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