Isolating Independent Effects of Diet/Energy Balance and Body Weight on Behavior and Metabolic Health
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ABSTRACT:
PROVIDER: PRJNA413547 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6145700.fastq.gz | Fastqsanger.gz | |||
| SRR6145710.fastq.gz | Fastqsanger.gz | |||
| SRR6145720.fastq.gz | Fastqsanger.gz | |||
| SRR6145730.fastq.gz | Fastqsanger.gz | |||
| SRR6145740.fastq.gz | Fastqsanger.gz |
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Project description:Associated with numerous metabolic and behavioral abnormalities, obesity is classified by metrics reliant on body weight (such as body mass index). However, overnutrition is the common cause of obesity, and may independently contribute to these obesity-related abnormalities. The goal of this study is to isolate ‘diet/energy balance’ effects independent from ‘body weight’ effects on various metabolic and behavioral parameters using the Diet Switch feeding paradigm in mice. [We conducted] unbiased gene expression analysis of the nutrient-sensing circumventricular hypothalamus [using RNA-seq]. Remarkably, only two genes responded to diet/energy balance (neuropeptide y [npy] and agouti-related peptide [agrp]), while others were related only to body weight. Furthermore, linear regression models revealed that npy and agrp showed similar modifiability by diet/energy balance and body weight compared to electroencephalographic-measured sleep/wake behavior.
2018-05-17 | GSE104709 | GEO
Project description:Psilocybin, and other serotonergic psychedelics, have re-emerged as therapeutics for neuropsychiatric disorders, including addiction. Psilocybin induces long-lasting effects on behavior, likely due to its profound ability to alter consciousness and augment neural connectivity and plasticity. Impaired synaptic plasticity in obesity contributes to ‘addictive-like’ behaviors, including heightened motivation for palatable food, and excessive food seeking and consumption. Here, we evaluate the effects of psilocybin on feeding behavior, energy metabolism and as a weight-lowering agent in mice. We demonstrate that a single dose of psilocybin substantially alters the prefrontal cortex transcriptome but has no acute or long-lasting effects on food intake or body weight in diet-induced obese mice or in genetic mouse models of obesity. Similarly, sub-chronic microdosing of psilocybin has no metabolic effects in obese mice and psilocybin does not augment glucagon-like peptide-1 (GLP-1) induced weight loss or enhance diet-induced weight loss. A single high dose of psilocybin reduces sucrose preference but fails to counter binge-like eating behavior. Although these preclinical data discourage clinical investigation, there may be nuances in the mode of action of psychedelic drugs that are difficult to capture in rodent models, and thus require human evaluation to uncover.
2022-08-17 | GSE209859 | GEO
Project description:Background and aims: Associated with numerous metabolic and behavioral abnormalities, obesity is classified by metrics reliant on body weight (such as body mass index). However, overnutrition is the common cause of obesity, and may independently contribute to these obesity-related abnormalities. Here, we use dietary challenges to parse apart the relative influence of diet and/or energy balance from body weight on various metabolic and behavioral outcomes.Materials and methods: Seventy male mice (mus musculus) were subjected to the diet switch feeding paradigm, generating groups with various body weights and energetic imbalances. Spontaneous activity patterns, blood metabolite levels, and unbiased gene expression of the nutrient-sensing ventral hypothalamus (using RNA-sequencing) were measured, and these metrics were compared using standardized multivariate linear regression models.Results: Spontaneous activity patterns were negatively related to body weight (p<0.0001) but not diet/energy balance (p = 0.63). Both body weight and diet/energy balance predicted circulating glucose and insulin levels, while body weight alone predicted plasma leptin levels. Regarding gene expression within the ventral hypothalamus, only two genes responded to diet/energy balance (neuropeptide y [npy] and agouti-related peptide [agrp]), while others were related only to body weight.Conclusions: Collectively, these results demonstrate that individual components of obesity-specifically obesogenic diets/energy imbalance and elevated body mass-can have independent effects on metabolic and behavioral outcomes. This work highlights the shortcomings of using body mass-based indices to assess metabolic health, and identifies novel associations between blood biomarkers, neural gene expression, and animal behavior following dietary challenges.
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Project description:Acute and long-term effects of psilocybin on energy balance and feeding behavior in mice
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Project description:The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo- or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IRS2. SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/IRS1/2 signaling complex. SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins. Accordingly, genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, and type 2 diabetes in mice. Neuron-specific overexpression of SH2B1β transgenes protects against diet-induced obesity and insulin resistance. SH2B1 in pancreatic β cells promotes β cell expansion and insulin secretion to counteract insulin resistance in obesity. Moreover, numerous SH2B1 mutations are genetically linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Unlike SH2B1, SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis. The metabolic function of the SH2B family is conserved from insects to humans.
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Project description:This trial studies how well weight management and health behavior intervention works in helping patients with hereditary breast and ovarian cancer and Lynch syndrome mutation carriers lose or maintain a healthy weight and lower their risk for cancer. Lifestyle behaviors such as physical activity, diet, and weight management may play a key role in preventing cancers and improving outcomes even in those with hereditary cancer syndromes.
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Project description:Study objectivesExcessive daytime sleepiness commonly affects obese people, even in those without sleep apnea, yet its causes remain uncertain. We sought to determine whether acute dietary changes could induce or rescue wake impairments independent of body weight.DesignWe implemented a novel feeding paradigm that generates two groups of mice with equal body weight but opposing energetic balance. Two subsets of mice consuming either regular chow (RC) or high-fat diet (HFD) for 8 w were switched to the opposite diet for 1 w. Sleep recordings were conducted at Week 0 (baseline), Week 8 (pre-diet switch), and Week 9 (post-diet switch) for all groups. Sleep homeostasis was measured at Week 8 and Week 9.ParticipantsYoung adult, male C57BL/6J mice.Measurements and resultsDifferences in total wake, nonrapid eye movement (NREM), and rapid eye movement (REM) time were quantified, in addition to changes in bout fragmentation/consolidation. At Week 9, the two diet switch groups had similar body weight. However, animals switched to HFD (and thus gaining weight) had decreased wake time, increased NREM sleep time, and worsened sleep/wake fragmentation compared to mice switched to RC (which were in weight loss). These effects were driven by significant sleep/wake changes induced by acute dietary manipulations (Week 8 → Week 9). Sleep homeostasis, as measured by delta power increase following sleep deprivation, was unaffected by our feeding paradigm.ConclusionsAcute dietary manipulations are sufficient to alter sleep and wakefulness independent of body weight and without effects on sleep homeostasis.
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Project description:Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.
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Project description:Pre- and postnatal calorie restriction is associated with postnatal growth restriction, reduced circulating leptin concentrations and perturbed energy balance. Hypothalamic regulation of energy balance demonstrates enhanced orexigenic (NPY, AgRP) and diminished anorexigenic (POMC, CART) neuropeptide expression (PN21) setting the stage for subsequent development of obesity. Leptin replenishment during the early postnatal period (PN2-PN8) led to reversing the hypothalamic orexigenic:anorexigenic neuropeptide ratio at PN21 by only reducing the orexigenic (NPY, AgRP) without affecting the anorexigenic (POMC, CART) neuropeptide expression. This hypothalamic effect was mediated via enhanced leptin receptor (ObRb) signaling that involved increased pSTAT3 but reduced PTP1B. This was further confirmed by an increase in body weight at PN21 in response to intracerebroventricular administration of antisense ObRb oligonucleotides (PN2-PN8). The change in the hypothalamic neuropeptide balance in response to leptin administration caused increased oxygen consumption, carbon dioxide production and physical activity which resulted in increased milk intake (PN14) with no change in body weight. This is in contrast to the reduction in milk intake with no effect on energy expenditure and physical activity observed in controls. We conclude that pre- and postnatal calorie restriction perturbs hypothalamic neuropeptide regulation of energy balance setting the stage for hyperphagia and reduced energy expenditure, hallmarks of obesity. Leptin in turn reverses this phenotype by increasing hypothalamic ObRb signaling (sensitivity) and affecting only the orexigenic arm of the neuropeptide balance.
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Project description:Experimentally establishing a group's body weight maintenance energy requirement is an important component of metabolism research. At present, the reference approach for measuring the metabolizable energy intake (MEI) from foods required for body weight maintenance in non-confined subjects is the doubly-labeled water (DLW)-total energy expenditure (TEE) method. In the current study, we evaluated an energy-intake weight balance method as an alternative to DLW that is more flexible and practical to apply in some settings.The hypothesis was tested that MEI from foods observed in a group of subjects maintaining a constant energy intake while keeping their weight within ±1 kg over 10 days is non-significantly different from DLW-measured TEE (TEEDLW). Six non-obese subjects evaluated as part of an earlier study completed the inpatient protocol that included a 3-day initial adjustment period.The group body weight coefficient of variation (X ± SD) during the 10-day balance period was 0.38 ± 0.10% and the slope of the regression line for body weight versus protocol day was non-significant at 1.8 g/day (R2, 0.002, p = 0.98). MEI from foods observed during the 10-day balance period (2390 ± 543 kcal/day) was non-significantly different (p = 0.96) from TEE measured by DLW (2373 ± 713 kcal/day); the MEI/TEEDLW ratio was 1.03 ± 0.15 (range 0.87-1.27) and the correlation between MEI from foods and TEEDLW was highly significant (R2, 0.88, p = 0.005).A carefully managed 10-day protocol that includes a constant MEI level from foods with weight stability (±1 kg) will provide a group's body weight maintenance energy requirement similar to that obtained with DLW. This approach opens the possibility of conducting affordable weight balance studies, shorter in duration than those previously reported, that are needed to answer a wide range of questions in clinical nutrition. Trial registration The study is registered at http://www.clinicaltrials.gov (NCT01672632; August 20, 2012).
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