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Inhibition of mitochondrial fission and iNOS in the dorsal vagal complex protects from overeating and weight gain.

ABSTRACT: The dorsal vagal complex (DVC) senses insulin and controls glucose homeostasis, feeding behaviour, and body weight. Three days of a high fat diet (HFD) in rats is sufficient to induce insulin resistance in the DVC and impair its ability to regulate feeding behaviour. HFD feeding is associated with increased dynamin-related protein 1 (Drp1)-dependent mitochondrial fission in the DVC. Higher Drp1 activity inhibits insulin signalling, although the exact mechanisms controlling body weight remain elusive. We show that Drp1 activation in DVC increased weight gain in rats and that Drp1 inhibition in HFD-fed rats reduced food intake, weight gain, and adipose tissue. Rats expressing active Drp1 in the DVC had higher levels of inducible nitric oxide synthase (iNOS), and knockdown of DVC iNOS in HFD-fed rats led to a reduction in food intake, weight gain, and adipose tissue. Finally, inhibiting mitochondrial fission in DVC astrocytes was sufficient to protect rats from HFD-dependent insulin resistance, hyperphagia, weight gain, and fat deposition. We revealed new molecular and cellular targets for brain regulation of whole-body metabolism, which could inform new strategies to combat obesity and diabetes.

SUBMITTER: Patel B

PROVIDER: S-EPMC7753200 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Inhibition of mitochondrial fission and iNOS in the dorsal vagal complex protects from overeating and weight gain.

Patel Bianca B New Lauryn E LE Griffiths Joanne C JC Deuchars Jim J Filippi Beatrice M BM

Molecular metabolism 20201120

<h4>Objectives</h4>The dorsal vagal complex (DVC) senses insulin and controls glucose homeostasis, feeding behaviour and body weight. Three-days of high-fat diet (HFD) in rats are sufficient to induce insulin resistance in the DVC and impair its ability to regulate feeding behaviour. HFD-feeding is associated with increased dynamin-related protein 1 (Drp1)-dependent mitochondrial fission in the DVC. We investigated the effects that altered Drp1 activity in the DVC has on feeding behaviour. Addit ...[more]

PMID: 33227495

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Project description:ContextThe role of diet composition in response to overeating and energy dissipation in humans is unclear.ObjectiveTo evaluate the effects of overconsumption of low, normal, and high protein diets on weight gain, energy expenditure, and body composition.Design, setting, and participantsA single-blind, randomized controlled trial of 25 US healthy, weight-stable male and female volunteers, aged 18 to 35 years with a body mass index between 19 and 30. The first participant was admitted to the inpatient metabolic unit in June 2005 and the last in October 2007.InterventionAfter consuming a weight-stabilizing diet for 13 to 25 days, participants were randomized to diets containing 5% of energy from protein (low protein), 15% (normal protein), or 25% (high protein), which they were overfed during the last 8 weeks of their 10- to 12-week stay in the inpatient metabolic unit. Compared with energy intake during the weight stabilization period, the protein diets provided approximately 40% more energy intake, which corresponds to 954 kcal/d (95% CI, 884-1022 kcal/d).Main outcome measuresBody composition was measured by dual-energy x-ray absorptiometry biweekly, resting energy expenditure was measured weekly by ventilated hood, and total energy expenditure by doubly labeled water prior to the overeating and weight stabilization periods and at weeks 7 to 8.ResultsOvereating produced significantly less weight gain in the low protein diet group (3.16 kg; 95% CI, 1.88-4.44 kg) compared with the normal protein diet group (6.05 kg; 95% CI, 4.84-7.26 kg) or the high protein diet group (6.51 kg; 95% CI, 5.23-7.79 kg) (P = .002). Body fat increased similarly in all 3 protein diet groups and represented 50% to more than 90% of the excess stored calories. Resting energy expenditure, total energy expenditure, and body protein did not increase during overfeeding with the low protein diet. In contrast, resting energy expenditure (normal protein diet: 160 kcal/d [95% CI, 102-218 kcal/d]; high protein diet: 227 kcal/d [95% CI, 165-289 kcal/d]) and body protein (lean body mass) (normal protein diet: 2.87 kg [95% CI, 2.11-3.62 kg]; high protein diet: 3.18 kg [95% CI, 2.37-3.98 kg]) increased significantly with the normal and high protein diets.ConclusionsAmong persons living in a controlled setting, calories alone account for the increase in fat; protein affected energy expenditure and storage of lean body mass, but not body fat storage.Trial registrationclinicaltrials.gov Identifier: NCT00565149.

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Inhibition of mitochondrial fission and iNOS in the dorsal vagal complex protects from overeating and weight gain.

Publications

Inhibition of mitochondrial fission and iNOS in the dorsal vagal complex protects from overeating and weight gain.

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