Obesity, adipocytes and insulin resistance—Friends for life?

Since the 1980s, there has been an alarming increase in obesity all over the world. A sedentary lifestyle and the uptake of energy-dense foods are drivers of this trend, exacerbated by changes in food systems and environments. In 2015, about 107 million children and 603 million adults were obese with an overall prevalence of 5% among children and 12% among adults.1 A high body mass index (BMI > 25) is the major risk factor for the development of insulin resistance, type 2 diabetes mellitus, cardiovascular diseases, some types of cancer and nevertheless poor life quality. 41% of BMI-related deaths were caused by cardiovascular diseases and accounted for 2.7 million deaths worldwide in 2015. Obesity is not only excessive fat accumulation around the body, but a condition characterized by metabolic changes with adverse effects on health.2 Those metabolic adaptions need to be further elucidated to understand the crosstalk between adipose tissue and other organ systems like skeletal muscle or liver to find potential targets for pharmacological interventions in obesity. Many publications from Acta Physiologica contribute to this challenging goal. Adipose tissue is nowadays more considered to be an endocrine organ than a simple energy depot protecting from cold and mechanical injury.3 It is involved in metabolic processes such as energy expenditure and food intake and has immune function. Inflammatory reactions, especially in the visceral white adipose tissue, play a major role during induction of insulin resistance and occur during excessive fat accumulation. Adipocyte-derived bioactive factors, referred to as adipokines, influence lipid and glucose metabolism, inflammation, vascular function and insulin sensitivity in the skeletal muscle. The distinct action of adipokines and especially the crosstalk with other organ systems seem to build the key mechanism in inducing the adverse effects on health in obese individuals. Rodriguez and colleagues reviewed the crosstalk between muscle cell-derived myokines and adipokines with a focus on fat browning in white adipose tissue.4 Contrary to white adipocytes with a single large lipid reservoir, brown adipocytes are smaller and have a polygonal shape with small lipid droplets and large spherical mitochondria networks. They express UCP1 to uncouple oxidative phosphorylation from ATP synthesis to produce heat. UCP1 activation could be an interesting target in obesity, since it is the major regulator of thermogenesis independent from shivering. The increase in energy expenditure by enhancing thermogenesis in brown adipose tissue and furthermore enlarging the amount of brown fat is an interesting approach in therapies of obesity. Exercise-induced fat browning is observed in numerous animal studies and leads to the identification of myokines from skeletal muscle as promoters of fat browning, for example, IL-6, irisin, BAIBA and meteorin-like. It is well known from rodent studies that the sympathetic nervous system regulates energy metabolism in brown and white adipose tissue mainly via adrenergic receptors (AR).5 AR activation is induced by cold stress, leptin or emotional stress. Decara and colleagues investigated β3-AR stimulation in rats through administration of the agonist CL316243. The combined administration resulted in reduction in food intake, increasing body weight gain and potentiates tissue-specific changes in cholesterol and lipid metabolism. Growing insulin resistance in obesity often leads to diabetes type 2 and metabolic syndrome. The underlying mechanism of obesity-induced skeletal muscle insulin resistance is still unclear, but there is growing evidence that mitochondria dynamics are involved during this process and insulin resistance may reflect mitochondrial defects.6-8 Kristensen et al propose a hypothetical model of the cellular processes. Reduced physical activity and energy demand lead to a shift in mitochondrial dynamics from interconnected networks to fragmentation. Additional lipid supply promotes lipotoxic effects on different insulin cascade steps. Approaches to reverse mitochondrial fission to fusion include studies of exercise in obese subjects. Mitochondrial dynamics were investigated in a small group of obese patients after 12 weeks of daily exercise by Axelrod et al.9 They found reduced FIS1, a regulator of fission and mitophagy, and decreased Parkin activation in skeletal muscle, a protein of the mitophagy pathway. Further beneficial effects of daily exercise were loss of body fat, reduced peripheral lipid and glucose accumulation and improved whole-body insulin sensitivity. Similar finding was described by Lund and colleagues in a study of high intensity interval training in elderly sedentary people. This kind of exercise induces improvements in indices of cardiometabolic health despite a lower amount of needed time in comparison to classic endurance training.10 High-intensity interval training of older obese subjects leads to improved whole-body insulin sensitivity, reduced total cholesterol and LDL cholesterol levels as well as loss of visceral fat mass.11 Lund et al investigated the relationship between insulin resistance and mitochondrial respiratory capacity in obese patients with and without diabetes type 2 before and after gastric bypass surgery. All patients lost weight and improved insulin resistance but without changes in the mitochondrial respiratory capacity; thus, both parameters are not linked with each other. In a study by Da Silva Teixeira, insulin sensitivity was measured in a mouse model of diet-induced obesity12 after treatment with 3,5-diiodothyronine (3,5-T2). The authors observed reduced body weight, fat mass and blood glucose, but no correlation with changes in classical markers of insulin sensitivity in sensitive target tissues, hepatic insulin response markers. Their conclusion is an enhancement of overall metabolic rate with increased energy demand and therefore inducing glucose utilization. Energy-sensitive tissues like muscles, brown and white fat tissue or liver offer the opportunity for pharmacological interventions in obesity.13 Decara and colleagues suggest the combined activation of glucagon-like peptide-1 (GLP1) receptor and β3-adrenergic receptor (β3-AR) receptors converging in their signalling pathways.14 The gut hormone GLP1 has anti-diabetic effects and stimulation of its receptor by the agonist liraglutide could be a promising treatment of obesity. The transient receptor potential ion channel M5 (TRPM5) could be a potential target for interventions in obesity. This receptor is expressed on pancreatic β-cells and type 2 taste receptor cells. TRPM5-ko mice show reduced weight gain and food intake during a high-fat diet, mainly by impaired tasting of sweetness.15 TRPM5 activation could furthermore provoke insulin secretion and prevention of diabetes type 2, but results from animal studies need to be transferred to human obesity. Examples for successful drug interventions in diabetes type 2 are metformin and SIRT1 activators like resveratrol.16, 17 Triggle and Ding review the beneficial effects of metformin with special focus on its impact on vascular complications, the main reason for high mortality in type 2 diabetes patients. SIRT1 activation improves insulin sensitivity, obesity and type 2 diabetes, but the underlying mechanism remains to be elucidated. Svensson et al showed in mice studies that resveratrol-induced improvements in glucose tolerance are independent from SIRT1 overexpression in skeletal muscles but probably driven by other organs regulating glucose homoeostasis like brain, pancreas and liver. Differentially expressed microRNAs between white adipocyte tissue from lean and obese individuals offer another opportunity for interventions in obesity. Nevertheless, the review of Vienberg et al emphasizes the difficult reproducibility of microRNA studies in obese patients to identify relevant candidate miRNAs.18 The treatment of obesity requires a complex therapy including diet modifications, exercise, nutritional education, cognitive behavioural therapy and surgical bariatric procedures.3 Drugs could be used to modify metabolic alterations in order to reduce comorbidities. The prevention of obesity is addressed to the underlying causal factors of obesity. The easy availability of highly processed, energy-dense and affordable food is a driver of obesity in almost all countries whereas the individual grade of obesity is determined by genetic and metabolic factors and furthermore local environmental factors.19 For that reason, prevention of obesity requires interventions on multiple levels to facilitate healthy behaviour. None. Bundesministerium für Bildung und Forschung (BMBF) iPS-Profiler, FKZ: 01EK1612B.