Abstract
In this era of increased obesity and diabetes prevalence, the browning of white adipose tissue (WAT) has emerged as a promising therapeutic target to induce weight loss and improve insulin ...sensitivity in this population. The browning process entails a shift in the WAT from primarily storing excess energy to the dissipation of energy as heat. However, this idealistic view of WAT browning being the savior of the metabolic syndrome has been criticized by studies in burn and cancer patients that have shown browning to be detrimental rather than beneficial. In fact, in the context of hypermetabolic states, the browning of WAT has presented with substantial clinical adverse outcomes related to cachexia, hepatic steatosis, and muscle catabolism. Therefore, the previous thought construct of understanding browning as an all-beneficial physiologic event has now been met with skepticism. In this review, we focus on current knowledge of browning of WAT and its adverse metabolic alterations during hypermetabolic states. We also discuss the regulators and signaling pathways involved in the browning process and their potential for being targeted by new or existing drugs to inhibit or alleviate browning, potentially leading to decreased hypermetabolism and improved clinical outcomes. Lastly, the imminent clinical applications of pharmacological agents are explored in the perspective of attenuating WAT browning and its associated adverse side effects reported in burn patients.
In conditions of hypermetabolism browning of adipose leads to cachexia and organ steatosis. Thus, drugs to inhibit browning in these patients can potentially attenuate some of these adverse effects.
Summary Improvements in acute burn care have enabled patients to survive massive burns that would have once been fatal. Now up to 70% of patients develop hypertrophic scars after burns. The ...functional and psychosocial sequelae remain a major rehabilitative challenge, decreasing quality of life and delaying reintegration into society. Approaches to optimise healing potential of burn wounds use targeted wound care and surgery to minimise the development of hypertrophic scarring. Such approaches often fail, and modulation of the established scar is continued although the optimal indication, timing, and combination of therapies have yet to be established. The need for novel treatments is paramount, and future efforts to improve outcomes and quality of life should include optimisation of wound healing to attenuate or prevent hypertrophic scarring, well-designed trials to confirm treatment efficacy, and further elucidation of molecular mechanisms to allow development of new preventive and therapeutic strategies.
Excessive scars form as a result of aberrations of physiologic wound healing and may arise following any insult to the deep dermis. By causing pain, pruritus and contractures, excessive scarring ...significantly affects the patient's quality of life, both physically and psychologically. Multiple studies on hypertrophic scar and keloid formation have been conducted for decades and have led to a plethora of therapeutic strategies to prevent or attenuate excessive scar formation. However, most therapeutic approaches remain clinically unsatisfactory, most likely owing to poor understanding of the complex mechanisms underlying the processes of scarring and wound contraction. In this review we summarize the current understanding of the pathophysiology underlying keloid and hypertrophic scar formation and discuss established treatments and novel therapeutic strategies.
The study of white adipose tissue (WAT) ‘browning’ has become a ‘hot topic’ in various acute and chronic metabolic conditions, based on the idea that WAT browning might be able to facilitate weight ...loss and improve metabolic health. However, this view cannot be translated into all areas of medicine. Recent studies identified effects of browning associated with adverse outcomes, and as more studies are being conducted, a very different picture has emerged about WAT browning and its detrimental effect in acute and chronic hypermetabolic conditions. Therefore, the notion that browning is supposedly beneficial may be inadequate. In this review we analyze how and why browning in chronic hypermetabolic associated diseases can be detrimental and lead to adverse outcomes.
A severe burn can trigger a hypermetabolic state which lasts for years following the injury, to the detriment of the patient. The drastic increase in metabolic demands during this phase renders it ...difficult to meet the body's nutritional requirements, thus increasing muscle, bone and adipose catabolism and predisposing the patient to a host of disorders such as multi-organ dysfunction and sepsis, or even death. Despite advances in burn care over the last 50 years, due to the multifactorial nature of the hypermetabolic phenomenon it is difficult if not impossible to precisely identify and pharmacologically modulate the biological mediators contributing to this substantial metabolic derangement. Here, we discuss biomarkers and molecules which play a role in the induction and mediation of the hypercatabolic condition post-thermal injury. Furthermore, this thorough review covers the development of the factors released after burns, how they induce cellular and metabolic dysfunction, and how these factors can be targeted for therapeutic interventions to restore a more physiological metabolic phenotype after severe thermal injuries. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju.
•Severe burns trigger chronic hypermetabolism.•Hypermetabolism increases incidences of infection and multi-organ dysfunction.•Cytokines, catecholamines and hormones induce the hypermetabolic state.•ER stress, abnormal mitochondria and insulin resistance post-burn are interconnected.•Beta blockade and glucose control agents can limit hypermetabolism post-thermal injury.
Hypermetabolism is the ubiquitous response to a severe burn injury, which was first described in the nineteenth century. Despite identification of important components of this complex response, ...hypermetabolism is still not well understood in its entirety. This article describes this incredibly fascinating response and the understanding we have gained over the past 100 years. Additionally, this article describes novel insights and delineates treatment options to modulate postburn hypermetabolism with the goal to improve outcomes of burn patients.
OBJECTIVE:The aim of this study was to compare the hypermetabolic, and inflammatory trajectories in burned adults to gain insight into the pathophysiological alterations and outcomes after injury.
...SUMMARY OF BACKGROUND DATA:Burn injury leads to a complex response that is associated with hypermetabolism, morbidity, and mortality. The underlying pathophysiology and the correlations between humoral changes and organ function have not been well delineated in adult burn patients.
METHODS:Burned adult patients (n = 1288) admitted to our center from 2006 to 2016 were enrolled in this prospective study. Demographics, clinical data, metabolic and inflammatory markers, hypermetabolism, organ function, and clinical outcomes were obtained throughout acute hospitalization. We then stratified patients according to burn size (<20%, 20% to 40%, and >40% total body surface area TBSA) and compared biomedical profiles and clinical outcomes for these patients.
RESULTS:Burn patients were hypermetabolic with elevated resting energy expenditure (REE) associated with increased browning of white adipose tissue from weeks 2 to 4. Hyperglycemia and hyperinsulinemia peaked 7 to 14 days after injury. Oral glucose tolerance and insulin resistance (QUICKI, HOMA2) tests further confirmed these findings with similar areas under the curve for moderate (20% to 40% TBSA) and severe burn (>40% TBSA). Lipid metabolism in sera revealed elevated pro-inflammatory stearic and linoleic acid, with complementary increases in anti-inflammatory free fatty acids. Similar increases were observed for inflammatory cytokines, chemokines, and metabolic hormones. White adipose tissue from the site of injury had increased ER stress, mitochondrial damage, and inflammasome activity, which was exacerbated with increasing burn severity.
CONCLUSIONS:In this large prospective trial, we delineated the complexity of the pathophysiologic responses postburn in adults and concluded that these profound responses are time and burn size dependent. Patients with medium-size (20% to 40% TBSA) burn demonstrated a very robust response that is similar to large burns.
Abstract Keloids and hypertrophic scars occur anywhere from 30 to 90% of patients, and are characterized by pathologically excessive dermal fibrosis and aberrant wound healing. Both entities have ...different clinical and histochemical characteristics, and unfortunately still represent a great challenge for clinicians due to lack of efficacious treatments. Current advances in molecular biology and genetics reveal new preventive and therapeutical options which represent a hope to manage this highly prevalent, chronic and disabling problem, with long-term beneficial outcomes and improvement of quality of life. While we wait for these translational clinical products to be marketed, however, it is imperative to know the basics of the currently existing wide array of strategies to deal with excessive scars: from the classical corticotherapy, to the most recent botulinum toxin and lasers. The main aim of this review paper is to offer a useful up-to-date guideline to prevent and treat keloids and hypertrophic scars.
Burn is accompanied by long-lasting immuno-metabolic alterations referred to as hypermetabolism that are characterized by a considerable increase in resting energy expenditure and substantial ...whole-body catabolism. In burned patients, the length and magnitude of the hypermetabolic state is the highest of all patients and associated with profoundly increased morbidity and mortality. Unfortunately, the mechanisms involved in hypermetabolism are essentially unknown. We hypothesized that the adipose tissue plays a central role for the induction and persistence of hypermetabolism post-burn injury. Here, we show that burn induces a switch in the phenotype of the subcutaneous fat from white to beige, with associated characteristics such as increased mitochondrial mass and UCP1 expression. Our results further demonstrate the significant role of catecholamines and interleukin-6 in this process. We conclude that subcutaneous fat remodeling and browning represent an underlying mechanism that explains the elevated energy expenditure in burn-induced hypermetabolism.
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•Burn injury results in browning of the subcutaneous fat in rodents and humans•Browning occurs beyond or after 10 days post-burn injury in humans•Markers of browning are reduced by the beta-blocker propranolol•IL-6 is required for browning in mice post-burn injury
Severe trauma such as burn injury is followed by a hypermetabolic state that is characterized by an elevation in energy expenditure and insulin resistance. Patsouris et al. show that severe burn injury results in browning of the subcutaneous fat; this may explain why these patients develop hypermetabolism.
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