Modulation of the Hypothalamic Nutrient Sensing Pathways by Sex and Early-Life Stress

Ruigrok, Silvie R.; Stöberl, Nina; Yam, Kit-Yi; Lucia, Chiara de; Lucassen, Paul J.; Thuret, Sandrine; Kőrösi, Anikó

doi:10.3389/fnins.2021.695367

Cited by 8 publications

(7 citation statements)

References 88 publications

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“…The mRNA levels of NPY and AgRP were higher in females compared to males, as previously reported ( 66 ), with this difference being more apparent in chow and HFDCH mice. Female rats are reported to consume a similar amount of palatable food independently of being satiated or hungry, with males adjusting their energy intake to their hunger state ( 67 ).…”

Section: Discussionsupporting

confidence: 87%

Sex Differences in Metabolic Recuperation After Weight Loss in High Fat Diet-Induced Obese Mice

et al. 2021

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Dietary intervention is a common tactic employed to curtail the current obesity epidemic. Changes in nutritional status alter metabolic hormones such as insulin or leptin, as well as the insulin-like growth factor (IGF) system, but little is known about restoration of these parameters after weight loss in obese subjects and if this differs between the sexes, especially regarding the IGF system. Here male and female mice received a high fat diet (HFD) or chow for 8 weeks, then half of the HFD mice were changed to chow (HFDCH) for 4 weeks. Both sexes gained weight (p < 0.001) and increased their energy intake (p < 0.001) and basal glycemia (p < 0.5) on the HFD, with these parameters normalizing after switching to chow but at different rates in males and females. In both sexes HFD decreased hypothalamic NPY and AgRP (p < 0.001) and increased POMC (p < 0.001) mRNA levels, with all normalizing in HFDCH mice, whereas the HFD-induced decrease in ObR did not normalize (p < 0.05). All HFD mice had abnormal glucose tolerance tests (p < 0.001), with males clearly more affected, that normalized when returned to chow. HFD increased insulin levels and HOMA index (p < 0.01) in both sexes, but only HFDCH males normalized this parameter. Returning to chow normalized the HFD-induced increase in circulating leptin (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.001, only in females) and IGFBP3 (p < 0.001), whereas free IGF1 levels remained elevated (p < 0.01). In males IGFBP2 decreased with HFD and normalized with chow (p < 0.001), with no changes in females. Although returning to a healthy diet improved of most metabolic parameters analyzed, fIGF1 levels remained elevated and hypothalamic ObR decreased in both sexes. Moreover, there was sex differences in both the response to HFD and the switch to chow including circulating levels of IGF2 and IGFBP2, factors previously reported to be involved in glucose metabolism. Indeed, glucose metabolism was also differentially modified in males and females, suggesting that these observations could be related.

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Section: Discussionsupporting

confidence: 87%

Sex Differences in Metabolic Recuperation After Weight Loss in High Fat Diet-Induced Obese Mice

et al. 2021

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“…Homeostatic regulation of feeding behaviors and energy balance is predominantly controlled by nutrient-sensing and endocrine-responsive signaling pathways in the hypothalamus ( 25 , 26 ). The hypothalamus consists of a group of nuclei that communicate with each other to coordinate the organism’s energy state via metabolic hormones originating in white adipose tissue (WAT), stomach and pancreas (leptin, insulin, ghrelin) and nutrients (glucose, fatty acids) ( 27 ). For example, the arcuate nucleus, located near the blood brain barrier, detects internal and peripheral energy signals such as glucose, insulin, leptin and ghrelin via specific receptors for these molecules ( 28 ).…”

Section: Introductionmentioning

confidence: 99%

Developmental exposure to indoor flame retardants and hypothalamic molecular signatures: Sex-dependent reprogramming of lipid homeostasis

Kozlova

Denys²,

Benedum³

et al. 2022

Front. Endocrinol.

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Polybrominated diphenyl ethers (PBDEs) are a class of flame-retardant organohalogen pollutants that act as endocrine/neuroendocrine disrupting chemicals (EDCs). In humans, exposure to brominated flame retardants (BFR) or other environmentally persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and novel organophosphate flame retardants has been associated with increasing trends of diabetes and metabolic disease. However, the effects of PBDEs on metabolic processes and their associated sex-dependent features are poorly understood. The metabolic-disrupting effects of perinatal exposure to industrial penta-PBDE mixture, DE-71, on male and female progeny of C57BL/6N mouse dams were examined in adulthood. Dams were exposed to environmentally relevant doses of PBDEs daily for 10 weeks (p.o.): 0.1 (L-DE-71) and 0.4 mg/kg/d (H-DE-71) and offspring parameters were compared to corn oil vehicle controls (VEH/CON). The following lipid metabolism indices were measured: plasma cholesterol, triglycerides, adiponectin, leptin, and liver lipids. L-DE-71 female offspring were particularly affected, showing hypercholesterolemia, elevated liver lipids and fasting plasma leptin as compared to same-sex VEH/CON, while L- and H-DE-71 male F1 only showed reduced plasma adiponectin. Using the quantitative Folch method, we found that mean liver lipid content was significantly elevated in L-DE-71 female offspring compared to controls. Oil Red O staining revealed fatty liver in female offspring and dams. General measures of adiposity, body weight, white and brown adipose tissue (BAT), and lean and fat mass were weighed or measured using EchoMRI. DE-71 did not produce abnormal adiposity, but decreased BAT depots in L-DE-71 females and males relative to same-sex VEH/CON. To begin to address potential central mechanisms of deregulated lipid metabolism, we used RT-qPCR to quantitate expression of hypothalamic genes in energy-regulating circuits that control lipid homeostasis. Both doses of DE-71 sex-dependently downregulated hypothalamic expression of Lepr, Stat3, Mc4r, Agrp, Gshr in female offspring while H-DE-71 downregulated Npy in exposed females relative to VEH/CON. In contrast, exposed male offspring displayed upregulated Stat3 and Mc4r. Intestinal barrier integrity was measured using FITC-dextran since it can lead to systemic inflammation that leads to liver damage and metabolic disease, but was not affected by DE-71 exposure. These findings indicate that maternal transfer of PBDEs disproportionately endangers female offspring to lipid metabolic reprogramming that may exaggerate risk for adult metabolic disease.

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“…There is a growing body of work showing that ELA induced differential effects in males and females (Naninck et al, 2015 ; Arp et al, 2016 ; Bath et al, 2017 ; Colich et al, 2017 ; Bondar et al, 2018 ; Ellis and Honeycutt, 2021 ; Ruigrok et al, 2021a , b ). Thus, we hypothesized that the impact of ELA on corticostriatal synapses would show sex-specific impairments.…”

Section: Resultsmentioning

confidence: 99%

“…To this end, our study begins to explore three questions that remain unanswered: (i) whether ELA impacts corticostriatal glutamate transmission in a manner that explains behavioral impairments; (ii) whether ELA affects the flexibility of mice to adopt different action selection strategies; and (iii) whether ELA impairs reversal learning. We also aim to address these questions in a sex-dependent manner on the basis of a plethora of studies showing differences in cognitive and emotional behaviors between male and female mice subjected to ELA (Colich et al, 2017 ; Ellis and Honeycutt, 2021 ; Bondar et al, 2018 ; Ruigrok et al, 2021a , b ). The sex-dependent differences in behaviors can be attributed to discrepancies in maternal care, where male mice receive more care than their female siblings (Oomen et al, 2009 ; van Hasselt et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Early life adversity impaired dorsal striatal synaptic transmission and behavioral adaptability to appropriate action selection in a sex-dependent manner

Carvalho

Khoja

Haile

et al. 2023

Front. Synaptic Neurosci.

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Early life adversity (ELA) is a major health burden in the United States, with 62% of adults reporting at least one adverse childhood experience. These experiences during critical stages of brain development can perturb the development of neural circuits that mediate sensory cue processing and behavioral regulation. Recent studies have reported that ELA impaired the maturation of dendritic spines on neurons in the dorsolateral striatum (DLS) but not in the dorsomedial striatum (DMS). The DMS and DLS are part of two distinct corticostriatal circuits that have been extensively implicated in behavioral flexibility by regulating and integrating action selection with the reward value of those actions. To date, no studies have investigated the multifaceted effects of ELA on aspects of behavioral flexibility that require alternating between different action selection strategies or higher-order cognitive processes, and the underlying synaptic transmission in corticostriatal circuitries. To address this, we employed whole-cell patch-clamp electrophysiology to assess the effects of ELA on synaptic transmission in the DMS and DLS. We also investigated the effects of ELA on the ability to update action control in response to outcome devaluation in an instrumental learning paradigm and reversal of action-outcome contingency in a water T-maze paradigm. At the circuit level, ELA decreased corticostriatal glutamate transmission in male but not in female mice. Interestingly, in DMS, glutamate transmission is decreased in male ELA mice, but increased in female ELA mice. ELA impaired the ability to update action control in response to reward devaluation in a context that promotes goal-directedness in male mice and induced deficits in reversal learning. Overall, our findings demonstrate the sex- and region-dependent effects of ELA on behavioral flexibility and underlying corticostriatal glutamate transmission. By establishing a link between ELA and circuit mechanisms underlying behavioral flexibility, our findings will begin to identify novel molecular mechanisms that can represent strategies for treating behavioral inflexibility in individuals who experienced early life traumatic incidents.

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Modulation of the Hypothalamic Nutrient Sensing Pathways by Sex and Early-Life Stress

Cited by 8 publications

References 88 publications

Sex Differences in Metabolic Recuperation After Weight Loss in High Fat Diet-Induced Obese Mice

Sex Differences in Metabolic Recuperation After Weight Loss in High Fat Diet-Induced Obese Mice

Developmental exposure to indoor flame retardants and hypothalamic molecular signatures: Sex-dependent reprogramming of lipid homeostasis

Early life adversity impaired dorsal striatal synaptic transmission and behavioral adaptability to appropriate action selection in a sex-dependent manner

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