Sex differences in high-fat diet-induced obesity, metabolic alterations and learning, and synaptic plasticity deficits in mice
Abstract
Obesity is a potential risk factor for cognitive deficits in the elder humans. Using a high‐fat diet (HFD)–induced obese mouse model, we investigated the impacts of HFD on obesity, metabolic and stress hormones, learning performance, and hippocampal synaptic plasticity. Both male and female C57BL/6J mice fed with HFD (3 weeks to 9–12 months) gained significantly more weights than the sex‐specific control groups. Compared with the obese female mice, the obese males had similar energy intake but developed more weight gains. The obese male mice developed hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia, but not hypertriglyceridemia. The obese females had less hyperinsulinemia and hypercholesterolemia than the obese males, and no hyperglycemia and hypertriglyceridemia. In the contextual fear conditioning and step‐down passive avoidance tasks, the obese male, but not female, mice showed poorer learning performance than their normal counterparts. These learning deficits were not due to sensorimotor impairment as verified by the open‐field and hot‐plate tests. Although, basal synaptic transmission characteristics (input–output transfer and paired‐pulse facilitation (PPF) ratio) were not significantly different between normal and HFD groups, the magnitudes of synaptic plasticity (long‐term potentiation (LTP) and long‐term depression (LTD)) were lower at the Schaffer collateral‐CA1 synapses of the hippocampal slices isolated from the obese male, but not female, mice, as compared with their sex‐specific controls. Our results suggest that male mice are more vulnerable than the females to the impacts of HFD on weight gains, metabolic alterations and deficits of learning, and hippocampal synaptic plasticity.
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Several strains of female mice are relatively resistant to obesity on a high-fat diet, but this protection can be removed by ovariectomy.
“Furthermore, unlike their male counterparts, several strains of female mice are relatively resistant to obesity on a high-fat diet [54, 55], but this protection can be removed by ovariectomy [56, 57].”
From Developmental programming of offspring adipose tissue biology and obesity risk (2021) · cites this paper as [55]
In mice on a high-fat diet, contextual fear conditioning and passive avoidance deficits were associated with reduced CA1 long-term potentiation and long-term depression.
“In mice receiving a high-fat diet, contextual fear conditioning and passive avoidance deficits were associated with reduced CA1 long-term potentiation and long-term depression.87”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [87]
Recent studies suggest that impaired angiogenesis in patients with hypercholesterolaemia parallels disturbances in synaptic plasticity, though evidence is limited.
“Although evidence is limited, recent studies suggest that impaired angiogenesis in patients with hypercholesterolaemia parallels disturbances in synaptic plasticity.”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [87]
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- Authors
- Hwang, L., Wang, C., Li, T., Chang, S., Lin, L., Chen, C., Chen, C., Liang, K., Ho, I., Yang, W., & Chiou, L.
- Affiliations
- Taipei Medical University (TW)
- National Taiwan University (TW)
- National Health Research Institutes (TW)
- Corresponding author
- Chiou, Lih‐Chu
- Venue
- Obesity
- Publisher
- Wiley
- Published
- 2010-03
- Volume
- 18
- Issue
- 3
- Pages
- 463-469
- ISSN
- 1930-7381 (ISSN-L)
- 1930-739X
- OpenAlex
- W2114381345
- Cited by
- 395
- References
- 41
- Citations by year
- 2026: 19 · 2025: 14 · 2024: 30 · 2023: 32 · 2022: 34 · 2021: 38 · 2020: 47 · 2019: 36 · 2018: 33 · 2017: 27 · 2016: 17 · 2015: 20 · 2014: 13 · 2013: 6 · 2012: 9
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Obesity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health Research Institutes
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- high-fat diet, diet-induced obesity, sex differences, learning deficits, hippocampal synaptic plasticity, long-term potentiation, long-term depression, Schaffer collateral-CA1 synapses, hyperinsulinemia, hypercholesterolemia, hyperleptinemia, hyperglycemia, contextual fear conditioning, passive avoidance, stress hormones, cognitive impairment
- MeSH terms
- Animals, Avoidance Learning, Energy Intake, Cognition Disorders, Conditioning, Classical, Dietary Fats, Disease Models, Animal, Fear, Female, Hippocampus, Hyperglycemia, Hyperinsulinism, Hyperlipidemias, Learning, Male, Metabolic Diseases, Mice, Inbred C57BL, Synaptic Transmission, Neuronal Plasticity, Obesity, Random Allocation, Sex Factors, Weight Gain, Long-Term Synaptic Depression, Mice
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