scholarly journals Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs

2019 ◽  
Vol 116 (21) ◽  
pp. 10547-10556 ◽  
Author(s):  
Gitalee Sarker ◽  
Wenfei Sun ◽  
David Rosenkranz ◽  
Pawel Pelczar ◽  
Lennart Opitz ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Small Rnas ◽  
Drugs Of Abuse ◽  
Brain Regions ◽  
High Fat ◽  
Potential Vector ◽  
Paternal Lineage ◽  
Metabolic Phenotypes ◽  
Enhanced Sensitivity ◽  
Maternal Overnutrition

There is a growing body of evidence linking maternal overnutrition to obesity and psychopathology that can be conserved across multiple generations. Recently, we demonstrated in a maternal high-fat diet (HFD; MHFD) mouse model that MHFD induced enhanced hedonic behaviors and obesogenic phenotypes that were conserved across three generations via the paternal lineage, which was independent of sperm methylome changes. Here, we show that sperm tRNA-derived small RNAs (tsRNAs) partly contribute to the transmission of such phenotypes. We observe increased expression of sperm tsRNAs in the F1 male offspring born to HFD-exposed dams. Microinjection of sperm tsRNAs from the F1-HFD male into normal zygotes reproduces obesogenic phenotypes and addictive-like behaviors, such as increased preference of palatable foods and enhanced sensitivity to drugs of abuse in the resultant offspring. The expression of several of the differentially expressed sperm tsRNAs predicted targets such as CHRNA2 and GRIN3A, which have been implicated in addiction pathology, are altered in the mesolimbic reward brain regions of the F1-HFD father and the resultant HFD-tsRNA offspring. Together, our findings demonstrate that sperm tsRNA is a potential vector that contributes to the transmission of MHFD-induced addictive-like behaviors and obesogenic phenotypes across generations, thereby emphasizing its role in diverse pathological outcomes.

scholarly journals Maternal overnutrition during critical developmental periods leads to different health adversities in the offspring: relevance of obesity, addiction and schizophrenia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gitalee Sarker ◽  
Kathrin Litwan ◽  
Rahel Kastli ◽  
Daria Peleg-Raibstein
Keyword(s):  
Early Development ◽  
High Fat Diet ◽  
Striatal Dopamine ◽  
High Fat ◽  
Metabolic Phenotypes ◽  
Poor Health Outcome ◽  
Effective Strategies ◽  
Enhanced Sensitivity ◽  
The Metabolic Syndrome ◽  
Maternal Overnutrition

AbstractMaternal overnutrition during sensitive periods of early development increases the risk for obesity and neuropsychiatric disorders later in life. However, it still remains unclear during which phases of early development the offspring is more vulnerable. Here, we investigate the effects of maternal high-fat diet (MHFD) at different stages of pre- or postnatal development and characterize the behavioral, neurochemical and metabolic phenotypes. We observe that MHFD exposure at pre-conception has no deleterious effects on the behavioral and metabolic state of the offspring. Late gestational HFD exposure leads to more prominent addictive-like behaviors with reduced striatal dopamine levels compared to early gestational HFD. Conversely, offspring exposed to MHFD during lactation display the metabolic syndrome and schizophrenia-like phenotype. The latter, is manifested by impaired sensory motor gating, and latent inhibition as well as enhanced sensitivity to amphetamine. These effects are accompanied by higher striatal dopamine levels. Together, our data suggest that MHFD exposure during specific stages of development leads to distinct neuropathological alterations that determine the severity and nature of poor health outcome in adulthood, which may provide insight in identifying effective strategies for early intervention.

scholarly journals Genetic Deletion of Syndecan-4 Alters Body Composition, Metabolic Phenotypes, and the Function of Metabolic Tissues in Female Mice Fed A High-Fat Diet (Running Title: Sdc4 Deficiency Affects Metabolic Phenotypes)

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2810 ◽  
Author(s):  
Maria De Luca ◽  
Denise Vecchie’ ◽  
Baskaran Athmanathan ◽  
Sreejit Gopalkrishna ◽  
Jennifer A. Valcin ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
High Fat Diet ◽  
Fatty Acid Synthase ◽  
Serum Triglyceride ◽  
Independent Study ◽  
Whole Body ◽  
Elderly Subjects ◽  
Sensitivity Index ◽  
High Fat ◽  
Metabolic Phenotypes

Syndecans are transmembrane proteoglycans that, like integrins, bind to components of the extracellular matrix. Previously, we showed significant associations of genetic variants in the Syndecan-4 (SDC4) gene with intra-abdominal fat, fasting plasma glucose levels, and insulin sensitivity index in children, and with fasting serum triglyceride levels in healthy elderly subjects. An independent study also reported a correlation between SDC4 and the risk of coronary artery disease in middle-aged patients. Here, we investigated whether deletion of Sdc4 promotes metabolic derangements associated with diet-induced obesity by feeding homozygous male and female Sdc4-deficient (Sdc4-/-) mice and their age-matched wild-type (WT) mice a high-fat diet (HFD). We found that WT and Sdc4-/- mice gained similar weight. However, while no differences were observed in males, HFD-fed female Sdc4-/- mice exhibited a higher percentage of body fat mass than controls and displayed increased levels of plasma total cholesterol, triglyceride, and glucose, as well as reduced whole-body insulin sensitivity. Additionally, they had an increased adipocyte size and macrophage infiltration in the visceral adipose tissue, and higher triglyceride and fatty acid synthase levels in the liver. Together with our previous human genetic findings, these results provide evidence of an evolutionarily conserved role of SDC4 in adiposity and its complications.

scholarly journals Lack of cardiac and high-fat diet induced metabolic phenotypes in two independent strains of Vegf-b knockout mice

2014 ◽  
Vol 4 (1) ◽  
Author(s):  
M. H. Dijkstra ◽  
E. Pirinen ◽  
J. Huusko ◽  
R. Kivelä ◽  
D. Schenkwein ◽  
...  
Keyword(s):  
Knockout Mice ◽  
High Fat Diet ◽  
High Fat ◽  
Metabolic Phenotypes

scholarly journals SIM1 Overexpression Partially Rescues Agouti Yellow and Diet-Induced Obesity by Normalizing Food Intake

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4542-4549 ◽  
Author(s):  
Bassil M. Kublaoui ◽  
J. Lloyd Holder ◽  
Kristen P. Tolson ◽  
Terry Gemelli ◽  
Andrew R. Zinn
Keyword(s):  
Food Intake ◽  
Energy Expenditure ◽  
Transgenic Mice ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Enhanced Sensitivity ◽  
Diet Induced Obesity ◽  
Melanocortin 4 Receptor ◽  
Obesity In Mice

Single-minded 1 (SIM1) mutations are associated with obesity in mice and humans. Haploinsufficiency of mouse Sim1 causes hyperphagic obesity with increased linear growth and enhanced sensitivity to a high-fat diet, a phenotype similar to that of agouti yellow and melanocortin 4 receptor knockout mice. To investigate the effects of increased Sim1 dosage, we generated transgenic mice that overexpress human SIM1 and examined their phenotype. Compared with wild-type mice, SIM1 transgenic mice had no obvious phenotype on a low-fat chow diet but were resistant to diet-induced obesity on a high-fat diet due to reduced food intake with no change in energy expenditure. The SIM1 transgene also completely rescued the hyperphagia and partially rescued the obesity of agouti yellow mice, in which melanocortin signaling is abrogated. Our results indicate that the melanocortin 4 receptor signals through Sim1 or its transcriptional targets in controlling food intake but not energy expenditure.

scholarly journals Obesity and Endocrine Dysfunction in Mice with Deletions of both Neuropeptide Y and Galanin

2004 ◽  
Vol 24 (7) ◽  
pp. 2978-2985 ◽  
Author(s):  
J. G. Hohmann ◽  
D. N. Teklemichael ◽  
D. Weinshenker ◽  
D. Wynick ◽  
D. K. Clifton ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Neuropeptide Y ◽  
High Fat Diet ◽  
Endocrine Dysfunction ◽  
Wild Type ◽  
High Fat ◽  
Metabolic Phenotypes ◽  
Obesity Phenotype ◽  
Compensatory Regulation

ABSTRACT Neuropeptide Y (NPY) and galanin have both been implicated in the regulation of body weight, yet mice bearing deletions of either of these molecules have unremarkable metabolic phenotypes. To investigate whether galanin and NPY might compensate for one another, we produced mutants lacking both neuropeptides (GAL−/−/NPY−/−). We found that male GAL−/−/NPY−/− mice ate significantly more and were much heavier (30%) than wild-type (WT) controls. GAL−/−/NPY−/− mice responded to a high-fat diet by gaining more weight than WT mice gain, and they were unable to regulate their weight normally after a change in diet. GAL−/−/NPY−/− mice had elevated levels of leptin, insulin, and glucose, and they lost more weight than WT mice during chronic leptin treatment. Galanin mRNA was increased in the hypothalamus of NPY−/− mice, providing evidence of compensatory regulation in single mutants. The disruption of energy balance observed in GAL−/−/NPY−/− double knockouts is not found in the phenotype of single knockouts of either molecule. The unexpected obesity phenotype may result from the dysregulation of the leptin and insulin systems that normally keep body weight within the homeostatic range.

The effect of metformin on neuronal activity in the appetite-regulating brain regions of mice fed a high-fat diet during an anorectic period

2016 ◽  
Vol 154 ◽  
pp. 184-190 ◽  
Author(s):  
Hyun-Ju Kim ◽  
Bo-Yeong Jin ◽  
Mi-Jeong Oh ◽  
Kyung-Ho Shin ◽  
Sang-Hyun Choi ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
High Fat Diet ◽  
Brain Regions ◽  
High Fat

scholarly journals Intermittent dietary fish oil supplementation prevents high fat diet‐induced enhanced sensitivity to the behavioral effects of quinpirole

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Nina M Beltran ◽  
Kayla I Galindo ◽  
Jose Echeverri ◽  
Caroline Hernandez‐Casner ◽  
Katherine M Serafine
Keyword(s):  
Fish Oil ◽  
High Fat Diet ◽  
Behavioral Effects ◽  
High Fat ◽  
Enhanced Sensitivity ◽  
Dietary Fish ◽  
Fish Oil Supplementation

scholarly journals Metformin Treatment Attenuates Brain Inflammation and Rescues Pacap/Vip Neuropeptide Alterations in Mice Fed a High-Fat Diet

2021 ◽  
Vol 22 (24) ◽  
pp. 13660
Author(s):  
Mawj Mandwie ◽  
Jocelyn Karunia ◽  
Aram Niaz ◽  
Kevin A. Keay ◽  
Giuseppe Musumeci ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Underlying Mechanism ◽  
Brain Regions ◽  
Brain Inflammation ◽  
Low Grade ◽  
Metformin Treatment ◽  
High Fat ◽  
Activation Markers ◽  
Beneficial Effects ◽  
Therapeutic Activities

High-fat diet (HFD)-induced comorbid cognitive and behavioural impairments are thought to be the result of persistent low-grade neuroinflammation. Metformin, a first-line medication for the treatment of type-2 diabetes, seems to ameliorate these comorbidities, but the underlying mechanism(s) are not clear. Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) are neuroprotective peptides endowed with anti-inflammatory properties. Alterations to the PACAP/VIP system could be pivotal during the development of HFD-induced neuroinflammation. To unveil the pathogenic mechanisms underlying HFD-induced neuroinflammation and assess metformin’s therapeutic activities, (1) we determined if HFD-induced proinflammatory activity was present in vulnerable brain regions associated with the development of comorbid behaviors, (2) investigated if the PACAP/VIP system is altered by HFD, and (3) assessed if metformin rescues such diet-induced neurochemical alterations. C57BL/6J male mice were divided into two groups to receive either standard chow (SC) or HFD for 16 weeks. A further HFD group received metformin (HFD + M) (300 mg/kg BW daily for 5 weeks) via oral gavage. Body weight, fasting glucose, and insulin levels were measured. After 16 weeks, the proinflammatory profile, glial activation markers, and changes within the PI3K/AKT intracellular pathway and the PACAP/VIP system were evaluated by real-time qPCR and/or Western blot in the hypothalamus, hippocampus, prefrontal cortex, and amygdala. Our data showed that HFD causes widespread low-grade neuroinflammation and gliosis, with regional-specific differences across brain regions. HFD also diminished phospho-AKT(Ser473) expression and caused significant disruptions to the PACAP/VIP system. Treatment with metformin attenuated these neuroinflammatory signatures and reversed PI3K/AKT and PACAP/VIP alterations caused by HFD. Altogether, our findings demonstrate that metformin treatment rescues HFD-induced neuroinflammation in vulnerable brain regions, most likely by a mechanism involving the reinstatement of PACAP/VIP system homeostasis. Data also suggests that the PI3K/AKT pathway, at least in part, mediates some of metformin’s beneficial effects.

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