Exercise enhances hepatic mitochondrial structure and function while preventing endoplasmic reticulum stress and metabolic dysfunction-associated steatotic liver disease in mice fed a high-fat diet.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has attracted increasing attention from the scientific community because of its severe but silent progression and the lack of specific treatment. Glucolipotoxicity triggers endoplasmic reticulum (ER) stress with decreased beta-oxidation and enhanced lipogenesis, promoting the onset of MASLD, whereas regular physical exercise can prevent MASLD by preserving ER and mitochondrial function. Thus, the hypothesis of this study was that high-intensity interval training (HIIT) could prevent the development of MASLD in high-fat (HF)-fed C57BL/6J mice by maintaining insulin sensitivity, preventing ER stress, and promoting beta-oxidation. Forty male C57BL/6J mice (3 months old) comprised 4 experimental groups: the control (C) diet group, the C diet + HIIT (C-HIIT) group, the HF diet group, and the HF diet + HIIT (HF-HIIT) group. HIIT sessions lasted 12 minutes and were performed 3 times weekly by trained mice. The diet and exercise protocols lasted for 10 weeks. The HIIT protocol prevented weight gain and maintained insulin sensitivity in the HF-HIIT group. A chronic HF diet increased ER stress-related gene and protein expression, but HIIT helped to maintain ER homeostasis, preserve mitochondrial ultrastructure, and maximize beta-oxidation. The increased sirtuin-1/peroxisome proliferator-activated receptor-gamma coactivator 1-alpha expression implies that HIIT enhanced mitochondrial biogenesis and yielded adequate mitochondrial dynamics. High hepatic fibronectin type III domain containing 5/irisin agreed with the antilipogenic and anti-inflammatory effects observed in the HF-HIIT group, reinforcing the antisteatotic effects of HIIT. Thus, we confirmed that practicing HIIT 3 times per week maintained insulin sensitivity, prevented ER stress, and enhanced hepatic beta-oxidation, impeding MASLD development in this mouse model even when consuming high energy intake from saturated fatty acids.

Time-dependent impact of a high-fat diet on the intestinal barrier of male mice.

BACKGROUND: Excessive saturated fat intake compromises the integrity of the intestinal mucosa, leading to low-grade inflammation, impaired mucosal integrity, and increased intestinal permeability, resulting in the migration of lipopolysaccharide (LPS) to other tissues. AIM: To evaluate the chronic effects (at 10 and 16 wk) of a high-fat diet (HFD) (with 50% energy as fat) on the phylogenetic gut microbiota distribution and intestinal barrier structure and protection in C57BL/6 mice. METHODS: Forty adult male mice were divided into four nutritional groups, where the letters refer to the type of diet (control and HFD or HF) and the numbers refer to the period (in weeks) of diet administration: Control diet for 10 wk, HFD for 10 wk, control diet for 16 wk, and HFD for 16 wk. After sacrifice, biochemical, molecular, and stereological analyses were performed. RESULTS: The HF groups were overweight, had gut dysbiosis, had a progressive decrease in occludin immunostaining, and had increased LPS concentrations. Dietary progression reduced the number of goblet cells per large intestine area and Mucin2 expression in the HF16 group, consistent with a completely disarranged intestinal ultrastructure after 16 wk of HFD intake. CONCLUSION: Chronic HFD intake causes overweight, gut dysbiosis, and morphological and functional alterations of the intestinal barrier after 10 or 16 wk. Time-dependent reductions in goblet cell numerical density and mucus production have emerged as targets for countering obesity-driven intestinal damage.

PPARα/γ synergism activates UCP1-dependent and -independent thermogenesis and improves mitochondrial dynamics in the beige adipocytes of high-fat fed mice.

OBJECTIVE: The aim of this study was to investigate the role of peroxisome proliferator-activated receptor (PPAR) activation (single PPARα or PPARγ, and dual PPARα/γ) on UCP1-dependent and -independent thermogenic pathways and mitochondrial metabolism in the subcutaneous white adipose tissue of mice fed a high-fat diet. METHODS: Male C57BL/6 mice received either a control diet (10% lipids) or a high-fat diet (HF; 50% lipids) for 12 wk. The HF group was divided to receive the treatments for 4 wk: HFγ (pioglitazone, 10 mg/kg), HFα (WY-14643, 3.5 mg/kg), and HFα/γ (tesaglitazar, 4 mg/kg). RESULTS: The HF group was overweight, insulin resistant, and had subcutaneous white adipocyte dysfunction. Treatment with PPARα and PPARα/γ reduced body mass, mitigated insulin resistance, and induced browning with increased UCP1-dependent and -independent thermogenesis activation and improved mitochondrial metabolism to support the beige adipocyte phenotype. CONCLUSION: PPARα and dual PPARα/γ activation recruited UCP1+ beige adipocytes and favored UCP1-independent thermogenesis, yielding body mass and insulin sensitivity normalization. Preserved mitochondrial metabolism emerges as a potential target for obesity treatment using PPAR agonists, with possible clinical applications.

Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas.

The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.

Exercise prevents obesity by reducing gut-derived inflammatory signals to brown adipocytes in mice.

Gut dysbiosis impairs nonshivering thermogenesis (NST) in obesity. The antiobesogenic effects of exercise training might involve the modulation of gut microbiota and its inflammatory signals to the brown adipose tissue (BAT). This study evaluated whether high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) prevent overweight through reduced gut-derived inflammatory signals to BAT in high-fat-fed mice. Sixty male C57BL/6 mice (3 months old) comprised six experimental groups: control (C) diet group, C diet + HIIT (C-HIIT) group, C diet + MICT (C-MICT) group, high-fat (HF) diet group, HF diet + HIIT (HF-HIIT) group, and HF diet + MICT (HF-MICT) group. The protocols lasted for 10 weeks. HIIT and MICT restored body mass, mitigated glucose intolerance, and prevented hyperinsulinemia in HF-trained groups. A chronic HF diet caused dysbiosis, but HIIT and MICT prevented gut dysbiosis and preserved tight junction (TJ) gene expression. HF-HIIT and HF-MICT groups exhibited a similar pattern of goblet cell distribution, agreeing with the decreased plasma lipopolysaccharide concentrations and interscapular BAT (iBAT) Lbp-Cd14-Tlr4 expression. The lowered Nlrp3 and Il1ß in the HF-HITT and HF-MICT groups complied with iBAT thermogenic capacity maintenance. This study shows reliable evidence that HIIT and MICT prevented overweight by restoring the diversity of the gut microbiota phyla and TJ gene expression, thereby reducing inflammatory signals to brown adipocytes with preserved thermogenic capacity. Both exercise modalities prevented overweight, but HIIT rescued Zo-1 and Jam-a gene expression, exerting more potent anti-inflammatory effects than MICT (reduced LPS concentrations), providing a sustained increase in thermogenesis with 78% less distance traveled.

Chronic Excessive Fructose Intake Maximizes Brown Adipocyte Whitening but Causes Similar White Adipocyte Hypertrophy Than a High-Fat Diet in C57BL/6 Mice.

Objective: This study aimed to evaluate the differential role of a high-fat diet (HF) or high-fructose diet (HFRU) on white adipose tissue and brown adipose tissue remodeling in C57BL/6 mice.Methods: The animals were randomly assigned to receive HF (50% of energy as lipids), HFRU (50% of energy as fructose), or a control diet (C, 10% of energy as lipids) for 12 weeks. Results: The HF group became overweight from the 7th week onwards, but both HF and HFRU groups showed hyperinsulinemia, oral glucose intolerance, and adverse adipose tissue remodeling. HF and HFRU groups showed interscapular brown adipose tissue whitening, tough the reduced QA [nuclei] suggested maximized brown adipocyte dysfunction due to the HFRU diet. In contrast, HF and HFRU diets exerted similar effects upon subcutaneous white adipocytes, with a similar average cross-sectional area. Immunohistochemistry confirmed the whitening enhancement with reduced UCP1 immunodensity in the HFRU group. Conclusion: In conclusion, HF and HFRU diets had indistinguishable effects upon white adipocyte morphology, but the HFRU diet provoked a more pronounced whitening than the HF diet after a 12-week protocol. These results point to the silent and harmful impact that excessive fructose has upon the metabolism of lean mice.

Progressive brown adipocyte dysfunction: Whitening and impaired nonshivering thermogenesis as long-term obesity complications.

Chronic obesity damages the cytoarchitecture of brown adipose tissue (BAT), leading to whitening of brown adipocytes and impaired thermogenesis, characterizing BAT dysfunction. Understanding the pathways of whitening progression can bring new targets to counter obesity. This study aimed to evaluate the chronic effect (12, 16, and 20 weeks) of a high-fat diet (50% energy as fat) upon energy expenditure, thermogenic markers, and pathways involved in BAT whitening in C57BL/6J mice. Sixty adult male mice comprised six nutritional groups, where the letters refer to the diet type (control, C or high-fat, HF), and the numbers refer to the period (in weeks) of diet administration: C12, HF12, C16, HF16, C20, and HF20. After sacrifice, biochemical, molecular, and stereological analyses addressed the outcomes. The HF groups had overweight, oral glucose intolerance, and hyperleptinemia, resulting in progressive whitening of BAT and decreased numerical density of nuclei per area of tissue compared to age-matched control groups. In addition, the whitening maximization was related to altered batokines gene expression, decreased nonshivering thermogenesis, and body temperature, resulting in low energy expenditure. The HF20 group showed enlarged adipocytes with stable and dysfunctional lipid droplets, followed by inflammation and ER stress. In conclusion, chronic HF diet intake caused time-dependent maximization of whitening with defective nonshivering thermogenesis. Long-term BAT dysfunction includes down-regulated vascularization markers, upregulated inflammasome activation, and ER stress markers.

A PPAR-alpha agonist and DPP-4 inhibitor mitigate adipocyte dysfunction in obese mice.

Obesity causes white and brown adipocyte dysfunction, reducing browning and stimulating whitening. Drugs that tackle adipocyte dysfunction through thermogenesis stimulation could be used to treat obesity. This study sought to address whether a combination of the PPAR-alpha agonist (WY14643) and DPP4i (linagliptin) potentiates browning and mitigates adipose tissue dysfunction, emphasizing the pathways related to browning induction and the underlying thermogenesis in high-fat-fed mice. Adult male C57BL/6 mice were randomly assigned to receive a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for 12 weeks. Experiment 1 aimed to evaluate whether 5 weeks of combined therapy was able to potentiate browning using a five-group design: C, HF, HFW (monotherapy with WY14643, 2.5 mg/kg body mass), HFL (monotherapy with linagliptin, 15 mg/kg body mass), and HFC (a combination of both drugs). Experiment 2 further addressed the pathways involved in browning maximization using a four-group study design: C, CC (C diet plus the drug combination), HF, and HFC (HF diet plus the drug combination). The HF group showed overweight, oral glucose intolerance, sWAT adipocyte hypertrophy, and reduced numerical density of nuclei per area of BAT confirming whitening. Only the combined treatment normalized these parameters in addition to body temperature increase, browning induction, and whitening rescue. The high expression of thermogenic marker genes parallel to reduced expression of inflammatory and endoplasmic reticulum stress genes mediated the beneficial findings. Hence, the PPAR-alpha agonist and DPP-4i combination is a promising target for obesity control by inducing functional brown adipocytes, browning of sWAT, and enhanced adaptive thermogenesis.

Endoplasmic reticulum stress as the basis of obesity and metabolic diseases: focus on adipose tissue, liver, and pancreas.

Obesity challenges lipid and carbohydrate metabolism. The resulting glucolipotoxicity  causes endoplasmic reticulum (ER) dysfunction, provoking the accumulation of immature proteins, which triggers the unfolded protein reaction (UPR) as an attempt to reestablish ER homeostasis. When the three branches of UPR fail to correct the unfolded/misfolded proteins, ER stress happens. Excessive dietary saturated fatty acids or fructose exhibit the same impact on the ER stress, induced by excessive ectopic fat accumulation or rising blood glucose levels, and meta-inflammation. These metabolic abnormalities can alleviate through dietary interventions. Many pathways are disrupted in adipose tissue, liver, and pancreas during ER stress, compromising browning and thermogenesis, favoring hepatic lipogenesis, and impairing glucose-stimulated insulin secretion within pancreatic beta cells. As a result, ER stress takes part in obesity, hepatic steatosis, and diabetes pathogenesis, arising as a potential target to treat or even prevent metabolic diseases. The scientific community seeks strategies to alleviate ER stress by avoiding inflammation, apoptosis, lipogenesis suppression, and insulin sensitivity augmentation through pharmacological and non-pharmacological interventions. This comprehensive review aimed to describe the contribution of excessive dietary fat or sugar to ER stress and the impact of this adverse cellular environment on adipose tissue, liver, and pancreas function.