Hepatic steatosis associated with decreased β-oxidation and mitochondrial function contributes to cell damage in obese mice after thermal injury

Objective Browning, the conversion of white adipose tissue (WAT) to a beige phenotype, has gained interest as a strategy to induce weight loss and improve insulin resistance in metabolic disorders. However, for hypermetabolic conditions stemming from burn trauma or cancer cachexia, browning is thought to contribute to energy wasting and supraphysiological nutritional requirements. Metformin's impact on this phenomenon and underlying mechanisms have not been explored. Methods We used both a murine burn model and human ex vivo adipose explants to assess metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)'s effects on the development of subcutaneous beige adipose. Enzymes involved in fat homeostasis and browning, as well as mitochondrial dynamics, were assessed to determine metformin's effects. Results Treatment with the biguanide metformin lowers lipolysis in beige fat by inducing protein phosphatase 2A (PP2A) independently of adenosine monophosphate kinase (AMPK) activation. Increased PP2A activity catalyzes the dephosphorylation of acetyl-CoA carboxylase (Ser 79) and hormone sensitive lipase (Ser 660), thus promoting fat storage and the “whitening” of otherwise lipolytic beige adipocytes. Moreover, co-incubation of metformin with the PP2A inhibitor okadaic acid countered the anti-lipolytic effects of this biguanide in human adipose. Additionally, we show that metformin does not activate this pathway in the WAT of control mice and that AICAR sustains the browning of white adipose, offering further evidence that metformin acts independently of this cellular energy sensor. Conclusions This work provides novel insights into the mechanistic underpinnings of metformin's therapeutic benefits and potential as an agent to reduce the lipotoxicity associated with hypermetabolism and adipose browning.

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“…Murine iWAT was fixed, sectioned and imaged at the University of Toronto Microscopy Imaging Laboratory, as described previously [24].…”

Section: Methodsmentioning

confidence: 99%

Metformin prevents the pathological browning of subcutaneous white adipose tissue

Auger

Knuth

Abdullahi

et al. 2019

Molecular Metabolism

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“…Equally, impaired insulin signaling also affects ER-mitochondria interactions, but here the results are also conflicting. An animal study showed that inhibition of AKT/mTOR signaling led to decreased ER-mitochondria contact in HFD-fed mice (115). In contrast, a greater number of hepatic ERmitochondria contact sites were observed in mice with either nutritionally (HFD) induced or genetically determined obesity compared with their respective lean controls (113).…”

Section: Altered Mam Integrity Induces Insulin Resistance In Periphermentioning

confidence: 99%

The Molecular Mechanisms Underlying Mitochondria-Associated Endoplasmic Reticulum Membrane-Induced Insulin Resistance

Cheng

Gang

et al. 2020

Front. Endocrinol.

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Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sites via what are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca2+ signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.

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“…25 Lipolysis occurs, but suppression of beta oxidation prevents lipid utility for energy and results in hepatic lipidosis. 26 The following burn trauma proteolysis exceeds protein synthesis and leads to skeletal muscle wasting. 6,27 Further increases in energy expenditure in burnassociated hypermetabolism are thought to be mediated by uncoupling protein 1 (UCP1) ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Nutritional management of a kitten with thermal burns and septicaemia

Birkbeck

Donaldson

Chan

2020

Journal of Feline Medicine and Surgery Open Reports

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Case summary A 3-month-old entire female British Shorthair cat presented for further management of thermal burns after falling into a bath of scalding water. On presentation to the primary care clinician the kitten was obtunded, markedly painful and relatively bradycardic, consistent with a state of shock. The haircoat was wet, with erythematous skin and sloughing from the digital pads and anal mucosa. The primary care clinician administered opioid analgesia, sedation, antibiotics and started intravenous (IV) fluid therapy prior to referral. On arrival to the referral hospital the kitten was obtunded with respiratory and cardiovascular stability but was overtly painful and resistant to handling. The kitten required intensive management with IV and regional analgesia, IV broad-spectrum antibiosis, IV fluid therapy, enteral nutrition and wound management, including surgical debridement and topical antibiotic therapy. Septicaemia developed during the hospitalisation. Multidrug-resistant Escherichia coli and Pseudomonas aeruginosa were cultured, and antibiosis was escalated to IV imipenem. Acute respiratory distress syndrome was suspected following the development of dyspnoea. Early enteral nutrition within 24 h of admission was initiated using an oesophageal feeding tube and a veterinary therapeutic liquid diet. Over the ensuing 72 h the kitten started voluntary intake of food alongside oesophageal tube feeds. The kitten experienced continued weight loss despite the provision of nutritional support to meet, and then later exceed, the estimated resting energy requirements. Caloric intake was gradually increased to a total of 438% of the calculated resting energy requirement using the most recent daily body weight, eventually resulting in stabilisation of weight loss and weight gain. Relevance and novel information There is limited published information on the nutritional management of veterinary patients with thermal burn injury. Hypermetabolic states related to burn injuries are induced and maintained by complex interactions of catecholamines, stress hormones and inflammatory cytokines on proteolysis, lipolysis and glycogenolysis. Secondary infections are common following burn injury and the subsequent proinflammatory state perpetuates hypermetabolism and catabolism. These states present a challenge in both predicting and providing adequate nutrition, particularly in a paediatric septic patient. This subset of patients should be monitored closely during hospitalisation to ensure body weight and condition are maintained (while taking into consideration hydration status), and caloric intake is adjusted accordingly to meet nutritional support goals. Extensive research exists regarding the nutritional requirements and metabolic derangements of people with thermal burns. However, the importance of maintaining body weight and body condition in veterinary burn patients, and the association between nutritional support and reduced morbidity and mortality, has not been investigated and remains to be elucidated.

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Hepatic steatosis associated with decreased β-oxidation and mitochondrial function contributes to cell damage in obese mice after thermal injury

Cited by 22 publications

References 48 publications

Metformin prevents the pathological browning of subcutaneous white adipose tissue

Metformin prevents the pathological browning of subcutaneous white adipose tissue

The Molecular Mechanisms Underlying Mitochondria-Associated Endoplasmic Reticulum Membrane-Induced Insulin Resistance

Nutritional management of a kitten with thermal burns and septicaemia

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