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Leptin production capacity determines food intake and susceptibility to obesity-induced diabetes in Oikawa-Nagao Diabetes-Prone and Diabetes-Resistant mice

Asai, Akira LU ; Nagao, Mototsugu LU ; Hayakawa, Koji ; Miyazawa, Teruo ; Sugihara, Hitoshi and Oikawa, Shinichi (2020) In Diabetologia 63(9). p.1836-1846
Abstract

AIMS/HYPOTHESIS: Obesity caused by overeating plays a pivotal role in the development of type 2 diabetes. However, it remains poorly understood how individual meal size differences are determined before the development of obesity. Here, we investigated the underlying mechanisms in determining spontaneous food intake in newly established Oikawa-Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice.

METHODS: Food intake and metabolic phenotypes of ON-DP and ON-DR mice under high-fat-diet feeding were compared from 5 weeks to 10 weeks of age. Differences in leptin status at 5 weeks of age were assessed between the two mouse lines. Adipose tissue explant culture was also performed to evaluate leptin production capacity in... (More)

AIMS/HYPOTHESIS: Obesity caused by overeating plays a pivotal role in the development of type 2 diabetes. However, it remains poorly understood how individual meal size differences are determined before the development of obesity. Here, we investigated the underlying mechanisms in determining spontaneous food intake in newly established Oikawa-Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice.

METHODS: Food intake and metabolic phenotypes of ON-DP and ON-DR mice under high-fat-diet feeding were compared from 5 weeks to 10 weeks of age. Differences in leptin status at 5 weeks of age were assessed between the two mouse lines. Adipose tissue explant culture was also performed to evaluate leptin production capacity in vitro.

RESULTS: ON-DP mice showed spontaneous overfeeding compared with ON-DR mice. Excessive body weight gain and fat accumulation in ON-DP mice were completely suppressed to the levels seen in ON-DR mice by pair-feeding with ON-DR mice. Deterioration of glucose tolerance in ON-DP mice was also ameliorated under the pair-feeding conditions. While no differences were seen in body weight and adipose tissue mass when comparing the two mouse lines at 5 weeks of age, the ON-DP mice had lower plasma leptin concentrations and adipose tissue leptin gene expression levels. In accordance with peripheral leptin status, ON-DP mice displayed lower anorexigenic leptin signalling in the hypothalamic arcuate nucleus when compared with ON-DR mice without apparent leptin resistance. Explant culture studies revealed that ON-DP mice had lower leptin production capacity in adipose tissue. ON-DP mice also displayed higher DNA methylation levels in the leptin gene promoter region of adipocytes when compared with ON-DR mice.

CONCLUSIONS/INTERPRETATION: The results suggest that heritable lower leptin production capacity plays a critical role in overfeeding-induced obesity and subsequent deterioration of glucose tolerance in ON-DP mice. Leptin production capacity in adipocytes, especially before the development of obesity, may have diagnostic potential for predicting individual risk of obesity caused by overeating and future onset of type 2 diabetes. Graphical abstract.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Adipocytes/metabolism, Adiponectin/genetics, Animals, CCAAT-Enhancer-Binding Proteins/genetics, Circadian Rhythm, Diabetes Mellitus, Type 2/etiology, Disease Models, Animal, Disease Susceptibility, Eating/physiology, Fatty Acid-Binding Proteins/genetics, Feeding Behavior/physiology, Glucose Tolerance Test, Hyperphagia/metabolism, Leptin/genetics, Locomotion, Mice, Obesity/complications, PPAR gamma/genetics
in
Diabetologia
volume
63
issue
9
pages
1836 - 1846
publisher
Springer
external identifiers
  • scopus:85086656159
  • pmid:32561946
ISSN
1432-0428
DOI
10.1007/s00125-020-05191-8
language
English
LU publication?
no
id
7a53bc4e-884b-43d0-ab4f-24290a5c4f44
date added to LUP
2023-01-12 01:55:03
date last changed
2024-03-06 00:37:29
@article{7a53bc4e-884b-43d0-ab4f-24290a5c4f44,
  abstract     = {{<p>AIMS/HYPOTHESIS: Obesity caused by overeating plays a pivotal role in the development of type 2 diabetes. However, it remains poorly understood how individual meal size differences are determined before the development of obesity. Here, we investigated the underlying mechanisms in determining spontaneous food intake in newly established Oikawa-Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice.</p><p>METHODS: Food intake and metabolic phenotypes of ON-DP and ON-DR mice under high-fat-diet feeding were compared from 5 weeks to 10 weeks of age. Differences in leptin status at 5 weeks of age were assessed between the two mouse lines. Adipose tissue explant culture was also performed to evaluate leptin production capacity in vitro.</p><p>RESULTS: ON-DP mice showed spontaneous overfeeding compared with ON-DR mice. Excessive body weight gain and fat accumulation in ON-DP mice were completely suppressed to the levels seen in ON-DR mice by pair-feeding with ON-DR mice. Deterioration of glucose tolerance in ON-DP mice was also ameliorated under the pair-feeding conditions. While no differences were seen in body weight and adipose tissue mass when comparing the two mouse lines at 5 weeks of age, the ON-DP mice had lower plasma leptin concentrations and adipose tissue leptin gene expression levels. In accordance with peripheral leptin status, ON-DP mice displayed lower anorexigenic leptin signalling in the hypothalamic arcuate nucleus when compared with ON-DR mice without apparent leptin resistance. Explant culture studies revealed that ON-DP mice had lower leptin production capacity in adipose tissue. ON-DP mice also displayed higher DNA methylation levels in the leptin gene promoter region of adipocytes when compared with ON-DR mice.</p><p>CONCLUSIONS/INTERPRETATION: The results suggest that heritable lower leptin production capacity plays a critical role in overfeeding-induced obesity and subsequent deterioration of glucose tolerance in ON-DP mice. Leptin production capacity in adipocytes, especially before the development of obesity, may have diagnostic potential for predicting individual risk of obesity caused by overeating and future onset of type 2 diabetes. Graphical abstract.</p>}},
  author       = {{Asai, Akira and Nagao, Mototsugu and Hayakawa, Koji and Miyazawa, Teruo and Sugihara, Hitoshi and Oikawa, Shinichi}},
  issn         = {{1432-0428}},
  keywords     = {{Adipocytes/metabolism; Adiponectin/genetics; Animals; CCAAT-Enhancer-Binding Proteins/genetics; Circadian Rhythm; Diabetes Mellitus, Type 2/etiology; Disease Models, Animal; Disease Susceptibility; Eating/physiology; Fatty Acid-Binding Proteins/genetics; Feeding Behavior/physiology; Glucose Tolerance Test; Hyperphagia/metabolism; Leptin/genetics; Locomotion; Mice; Obesity/complications; PPAR gamma/genetics}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1836--1846}},
  publisher    = {{Springer}},
  series       = {{Diabetologia}},
  title        = {{Leptin production capacity determines food intake and susceptibility to obesity-induced diabetes in Oikawa-Nagao Diabetes-Prone and Diabetes-Resistant mice}},
  url          = {{http://dx.doi.org/10.1007/s00125-020-05191-8}},
  doi          = {{10.1007/s00125-020-05191-8}},
  volume       = {{63}},
  year         = {{2020}},
}