Lipid droplet structural remodeling in adipose tissue upon caloric excess

Excess calories are stored as triacylglycerols (TAG) and cholesteryl esters (CE) in lipid droplets (LD), and during obesity, LD expansion occurs. X-ray scattering of adipose tissue uncovered that LDs comprise two TAG packing domains: a disordered core and a multilamellar shell. The number of TAG layers increases upon diet-induced obesity and is adipose depot-specific. Further, collagen was highly oriented in brown but randomly dispersed in white fat. We discovered that the body's surfactant, bile acids (BAs) stimulate remodeling of LD size. Deleting the BA receptor, Farnesoid X receptor (FXR) reduced a hydrophilic BA, beta muricholic acid (beta-MCA), and enlarged the adipocytes. BA composition is a critical determinant of overall hydrophobicity index and solubilization ability. Accordingly, we found that the obesogenic diet reduced a hydrophobic BA, chenodeoxycholic acid (CDCA). Taken together, these findings implicate that BAs, tissue niches, and diet influence LD structural remodeling.

Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms1,2. Conversely, the endogenous regulation and secretion of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent studies that prolonged, moderate- to high-intensity endurance exercise substantially increases circulating GDF15, in a time-dependent and reversible fashion, to peak levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice following forced treadmill running and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. Compared to other metabolic stressors, like fasting, acute high-fat diet feeding, severe caloric excess and temperature changes, exercise has a greater impact on circulating GDF15 levels. However, whereas pharmacological GDF15 inhibits appetite and suppresses wheel running activity via GFRAL, in response to exercise, the physiological induction of GDF15 does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. However, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for exercise aversion/fatigue. Thus, the physiological effects of GDF15 as an exerkine remain elusive.

Systemically-delivered biodegradable PLGA alters gut microbiota and induces transcriptomic reprogramming in the liver in an obesity mouse model

Biodegradable materials, including the widely used poly (lactic-co-glycolic acid) (PLGA) nanoparticles contained in slow-release drug formulations, scaffolds and implants, are ubiquitous in modern biomedicine and are considered inert or capable of being metabolized through intermediates such as lactate. However, in the presence of metabolic stress, such as in obesity, the resulting degradation products may play a detrimental role, which is still not well understood. We evaluated the effect of intravenously-administered PLGA nanoparticles on the gut-liver axis under conditions of caloric excess in C57BL/6 mice. Our results show that PLGA nanoparticles accumulate and cause gut acidification in the cecum, accompanied by significant changes in the microbiome, with a marked decrease of Firmicutes and Bacteroidetes. This was associated with transcriptomic reprogramming in the liver, with a downregulation of mitochondrial function, and an increase in key enzymatic, inflammation and cell activation pathways. No changes were observed in systemic inflammation. Metagenome analysis coupled with publicly available microarray data suggested a mechanism of impaired PLGA degradation and intestinal acidification confirming an important enterohepatic axis of metabolite-microbiome interaction resulting in maintenance of metabolic homeostasis. Thus, our results have important implications for the investigation of PLGA use in metabolically-compromised clinical and experimental settings.

Effects of a four-week very low-carbohydrate high-fat diet on biomarkers of inflammation: Non-randomised parallel-group study

Background: It is commonly assumed that increased dietary fat and/or caloric excess induces chronic inflammatory processes, since the association between obesity and chronic adipose tissue with systemic inflammation has been shown previously. As far as we know, the reported health benefits of a VLCHF or ketogenic diet have not adequately involved an evaluation of biomarkers of inflammation. Aim: This study investigated the effects of a four-week very low-carbohydrate high-fat (VLCHF) diet in healthy young individuals on biomarkers of inflammation. Methods: Eighteen moderately trained males (age 23.8 ± 2.1 years) were assigned to two groups. One group switched to a non-standardised VLCHF diet for four weeks, while the second group remained consuming their normal habitual diet (HD). Biomarkers of inflammation (adiponectin, leptin, resistin and interleukin-6) and substrate metabolism (fasting glucose and triacylglyceride concentrations) were analysed from blood at baseline and after four weeks. Results: There was moderate evidence for substantial changes in leptin serum concentrations in the VLCHF group, with small to large decreases compared to the HD group after four weeks (effect size = 0.78, 95% CI 0.42, 0.93, p = 0.008; Bayes Factor10 = 5.70). No substantial between-group change differences over time were found across any other biomarkers. Conclusions: A four-week period of consuming a VLCHF diet in healthy young men was not associated with any considerable changes in markers of inflammation but showed evidence for lowered serum leptin concentrations relative to the HD group.

Preoperative Nutritional Management

Malnutrition in the developed world generally comprises both excess of calories with poor macronutrient (carbohydrate—protein—fat) proportioning, and deficit of multiple micronutrients (vitamins, minerals, and phytonutrients). These excesses, deficits, and imbalances all confer health risks, and many are associated with the development of systemic inflammation and chronic pain. In the perioperative context, malnutrition is also associated with suboptimal surgical outcomes; from a nutrient deficiency standpoint, compromised wound healing and increased incidence of infections are seen. From a caloric excess standpoint, obesity confers markedly increased perioperative morbidity and mortality. Most of the evidence-based literature supports the use of so-called immunonutrition preoperatively in populations at risk. As with all of the lifestyle modification issues discussed in this book, enhancement of patients’ intrinsic motivation and thoughtful identification and replacement of maladaptive habits with better alternatives are of the essence.

Fisetin supplementation prevents high fat diet-induced diabetic nephropathy by repressing insulin resistance and RIP3-regulated inflammation

Obesity-related renal disease is related to caloric excess promoting deleterious cellular responses.

Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in mice

Phosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.

Do adipose tissue macrophages promote insulin resistance or adipose tissue remodelling in humans?

In diet induced and genetically obese rodent models, adipose tissue is associated with macrophage infiltration, which promotes a low grade inflammatory state and the development of insulin resistance. In humans, obesity is also closely linked with macrophage infiltration in adipose tissue, a pro-inflammatory phenotype and insulin resistance. However, whether macrophage infiltration is a direct contributor to the development of insulin resistance that occurs in response to weight gain, or is a later consequence of the obese state is unclear. There are a number of concomitant changes that occur during adipose tissue expansion, including the number and size of adipocytes, the vasculature and the extracellular matrix. In this review, we will examine evidence for and against the role of macrophage recruitment into adipose tissue in promoting the development of insulin resistance in rodents and humans, as well as discuss the emerging role of macrophages in mediating healthy adipose tissue expansion during periods of caloric excess.