Objective Insulin action in the brain controls metabolism and brain function, which is linked to proper mitochondrial function. Conversely, brain insulin resistance associates with mitochondrial stress and metabolic and neurodegenerative diseases. In the present study, we aimed to decipher the impact of hypothalamic insulin action on mitochondrial stress responses, function and metabolism. Methods To investigate the crosstalk of insulin action and mitochondrial stress responses (MSR), namely the mitochondrial unfolded protein response (UPRmt) and integrated stress response (ISR), qPCR, western blotting, and mitochondrial activity assays were performed. These methods were used to analyze the hypothalamic cell line CLU183 treated with insulin in the presence or absence of the insulin receptor as well as in mice fed a high fat diet (HFD) for three days and STZ-treated mice without or with insulin therapy. Intranasal insulin treatment was used to investigate the effect of acute brain insulin action on metabolism and mitochondrial stress responses. Results Acute HFD feeding reduces hypothalamic mitochondrial stress responsive gene expression of Atf4 , Chop , Hsp60 , Hsp10 , ClpP , and Lonp1 in C57BL/6N mice. We show that insulin via ERK activation increases the expression of MSR genes in vitro as well as in the hypothalamus of streptozotocin-treated mice. This regulation propagates mitochondrial function by controlling mitochondrial proteostasis and prevents excessive autophagy under serum deprivation. Finally, short-term intranasal insulin treatment activates MSR gene expression in the hypothalamus of HFD-fed C57BL/6N mice and reduces food intake and body weight development. Conclusions We define hypothalamic insulin action as a novel master regulator of MSR, ensuring proper mitochondrial function by controlling mitochondrial proteostasis and regulating metabolism.
The prevalence of obesity and its co-morbidities such as insulin resistance and type 2 diabetes are tightly linked to increased ingestion of palatable fat enriched food. Thus, it seems intuitive that the brain senses elevated amounts of fatty acids (FAs) and affects adaptive metabolic response, which is connected to mitochondrial function and insulin signaling. This review will address the effect of dietary FAs on brain insulin and mitochondrial function with a special emphasis on the impact of different FAs on brain function and metabolism.
Overconsumption of high-fat and cholesterol-containing diets is detrimental for metabolism and mitochondrial function, causes inflammatory responses and impairs insulin action in peripheral tissues. Dietary fatty acids can enter the brain to mediate the nutritional status, but also to influence neuronal homeostasis. Yet, it is unclear whether cholesterol-containing high-fat diets (HFDs) with different combinations of fatty acids exert metabolic stress and impact mitochondrial function in the brain. To investigate whether cholesterol in combination with different fatty acids impacts neuronal metabolism and mitochondrial function, C57BL/6J mice received different cholesterol-containing diets with either high concentrations of long-chain saturated fatty acids or soybean oil-derived poly-unsaturated fatty acids. In addition, CLU183 neurons were stimulated with combinations of palmitate, linoleic acid and cholesterol to assess their effects on metabolic stress, mitochondrial function and insulin action. The dietary interventions resulted in a molecular signature of metabolic stress in the hypothalamus with decreased expression of occludin and subunits of mitochondrial electron chain complexes, elevated protein carbonylation, as well as c-Jun N-terminal kinase (JNK) activation. Palmitate caused mitochondrial dysfunction, oxidative stress, insulin and insulin-like growth factor-1 (IGF-1) resistance, while cholesterol and linoleic acid did not cause functional alterations. Finally, we defined insulin receptor as a novel negative regulator of metabolically stress-induced JNK activation.
Brain insulin action regulates metabolism and behavior. Conversely in diabetes, brain insulin resistance associates with obesity and behavioral abnormalities. Intranasal insulin (INI) treatment activates brain insulin signaling in rodents and humans with a more prominent effect on metabolism in males. Recently, we have shown that INI treatment reduces diet-induced high fat diet (HFD) weight gain in males. Here, we investigated whether INI treatment reduces metabolic and behavioral abnormalities in males and females fed a HFD. We investigated the effect of 1h 1.75U INI treatment on metabolism and behavior in 12 weeks old C57BL/6N male and female mice fed a normal chow diet (NCD) and HFD for two weeks. We analyzed brain insulin signaling using ELISA, qPCR and western blot technique and assessed metabolic parameters as well as behavior using a dark-light box and novelty-suppressed feeding test. We show that acute INI treatment activates the insulin cascade in a region-dependent manner with highest activation in olfactory bulbus, caudate putamen and hypothalamus in males. INI treatment caused a two-fold increase in insulin levels in the cerebrospinal fluid (CSF) without altering blood glucose and insulin levels. INI reduced anxiety in males fed a NCD using a dark-light box test and novelty-suppressed feeding test. Yet, INI treatment did not alter insulin signaling and behavior in mice fed a HFD. Though male and female mice exhibited equal amounts of insulin receptor signaling proteins in the brain, INI treatment did not alter food intake, body weight gain or behavior in females fed a NCD or a HFD. In females, basal insulin levels in the CSF were comparable to insulin levels of INI-treated males and did not drastically increase further after INI treatment indicating optimal insulin action under basal conditions. Overall, we show that INI treatment activates the insulin signaling throughout the brain and improves in a sex-dependent manner metabolism and behavior only in healthy conditions. Disclosure C. Chudoba: None. A. Kleinridders: None. Funding German Federal Ministry of Education and Research; State of Brandenburg (82DZD00302)
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