Abstract
ObjectivesThe 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. Additionally, we aimed to uncover the molecular events and the neuronal cell populations associated with DVC insulin sensing and resistance. MethodsEight-week-old male Sprague Dawley rats received DVC stereotactic surgery for brain infusion to facilitate the localised administration of insulin or viruses to express mutated forms of Drp1 or to knockdown inducible nitric oxide synthase (iNOS) in the NTS of the DVC. High-Fat diet feeding was used to cause insulin resistance and obesity. ResultsWe showed that Drp1 activation in the DVC increases weight gain in rats and 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 iNOS and knockdown of DVC iNOS in HFD-fed rats led to a reduction of 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. ConclusionWe uncovered new molecular and cellular targets for brain regulation of whole-body metabolism, which could inform new strategies to combat obesity and diabetes.
Highlights
Diabetes and obesity are epidemic diseases with rising incidence across the world
Increased mitochondrial fission was observed in the dorsal vagal complex (DVC) of high-fat diet (HFD)-fed rats (Filippi et al, 2017) and we sought to determine whether HFD-dependent increased mitochondrial fission in the DVC affects the ability of insulin to lower food intake
We have shown that increasing DVC mitochondrial fission triggers insulin resistance, causes hyperphagia, increases body weight gain and fat deposition (Fig 6a)
Summary
Diabetes and obesity are epidemic diseases with rising incidence across the world. Overnutrition is the predominant pathogenic inducer of insulin resistance, which is mainly caused by increased circulating levels of glucose, free fatty acids and amino acids (Dresner et al, 1999; Roden et al, 1996). The CNS is instrumental in regulating metabolic homeostasis as it receives and processes peripheral inputs reporting the metabolic status of an individual and signals back to peripheral organs to maintain energy balance Subtle imbalance of these homeostatic processes can lead to metabolic diseases with obesity and diabetes causing a major human health problem and a strain in health services worldwide. Overnutrition has a large impact on the CNS and leads to a loss of the brain’s ability to sense changes in hormone and nutrient levels This has a dramatic effect on metabolic homeostasis where individuals struggle to maintain whole-body energy balance, leading to obesity and the development of diabetes (Timper & Brüning, 2017; Cai, 2013). Restoring the brain’s ability to modulate metabolic functions could be very important to prevent the negative outcomes of obesity and diabetes
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