Background: Like all healthy ecosystems, richness of microbiota species characterizes the GI microbiome in healthy individuals. Conversely, a loss in species diversity is a common finding in several disease states. This biome is flooded with energy in the form of undigested and partially digested foods, and in some cases drugs and dietary supplements. Each microbiotic species in the biome transforms that energy into new molecules, which may signal messages to physiological systems of the host.
Scope of review: Dietary choices select substrates for species, providing a competitive advantage over other GI microbiota. The more diverse the diet, the more diverse the microbiome and the more adaptable it will be to perturbations. Unfortunately, dietary diversity has been lost during the past 50 years and dietary choices that exclude food products from animals or plants will narrow the GI microbiome further.
Major conclusions: Additional research into expanding gut microbial richness by dietary diversity is likely to expand concepts in healthy nutrition, stimulate discovery of new diagnostics, and open up novel therapeutic possibilities.[Hide abstract]
Background: High density lipoproteins (HDLs) are thought to be atheroprotective and to reduce the risk of cardiovascular disease (CVD). Besides their antioxidant, antithrombotic, anti-inflammatory, anti-apoptotic properties in the vasculature, HDLs also improve glucose metabolism in skeletal muscle.
Scope of review: Herein, we review the functional role of HDLs to improve metabolic disorders, especially those involving insulin resistance and to induce regression of CVD with a particular focus on current pharmacological treatment options as well as lifestyle interventions, particularly exercise.
Major conclusions: Functional properties of HDLs continue to be considered important mediators to reverse metabolic dysfunction and to regress atherosclerotic cardiovascular disease. Lifestyle changes are often recommended to reduce the risk of CVD, with exercise being one of the most important of these. Understanding how exercise improves HDL function will likely lead to new approaches to battle the expanding burden of obesity and the metabolic syndrome.[Hide abstract]
Objective: Obesity represents a major risk factor for the development of type 2 diabetes mellitus, atherosclerosis and certain cancer entities. Treatment of obesity is hindered by the long-term maintenance of initially reduced body weight, and it remains unclear whether all pathologies associated with obesity are fully reversible even upon successfully maintained weight loss.
Methods: We compared high fat diet-fed, weight reduced and lean mice in terms of body weight development, adipose tissue and liver insulin sensitivity as well as inflammatory gene expression. Moreover, we assessed similar parameters in a human cohort before and after bariatric surgery.
Results: Compared to lean animals, mice that demonstrated successful weight reduction showed increased weight gain following exposure to ad libitum control diet. However, pair-feeding weight-reduced mice with lean controls efficiently stabilized body weight, indicating that hyperphagia was the predominant cause for the observed weight regain. Additionally, whereas glucose tolerance improved rapidly after weight loss, systemic insulin resistance was retained and ameliorated only upon prolonged pair-feeding. Weight loss enhanced insulin action and resolved pro-inflammatory gene expression exclusively in the liver, whereas visceral adipose tissue displayed no significant improvement of metabolic and inflammatory parameters compared to obese mice. Similarly, bariatric surgery in humans (n = 55) resulted in massive weight reduction, improved hepatic inflammation and systemic glucose homeostasis, while adipose tissue inflammation remained unaffected and adipocyte-autonomous insulin action only exhibit minor improvements in a subgroup of patients (42%).
Conclusions: These results demonstrate that although sustained weight loss improves systemic glucose homeostasis, primarily through improved inflammation and insulin action in liver, a remarkable obesogenic memory can confer long-term increases in adipose tissue inflammation and insulin resistance in mice as well as in a significant subpopulation of obese patients.[Hide abstract]
Objective: Non-shivering thermogenesis in brown adipose tissue (BAT) plays a central role in energy homeostasis. Thioesterase superfamily member 1 (Them1), a BAT-enriched long chain fatty acyl-CoA thioesterase, is upregulated by cold and downregulated by warm ambient temperatures. Them1-/- mice exhibit increased energy expenditure and resistance to diet-induced obesity and diabetes, but the mechanistic contribution of Them1 to the regulation of cold thermogenesis remains unknown.
Methods: Them1-/- and Them1+/+ mice were subjected to continuous metabolic monitoring to quantify the effects of ambient temperatures ranging from thermoneutrality (30 °C) to cold (4 °C) on energy expenditure, core body temperature, physical activity and food intake. The effects of Them1 expression on O2 consumption rates, thermogenic gene expression and lipolytic protein activation were determined ex vivo in BAT and in primary brown adipocytes.
Results: Them1 suppressed thermogenesis in mice even in the setting of ongoing cold exposure. Without affecting thermogenic gene transcription, Them1 reduced O2 consumption rates in both isolated BAT and primary brown adipocytes. This was attributable to decreased mitochondrial oxidation of endogenous but not exogenous fatty acids.
Conclusions: These results show that Them1 may act as a break on uncontrolled heat production and limit the extent of energy expenditure. Pharmacologic inhibition of Them1 could provide a targeted strategy for the management of metabolic disorders via activation of brown fat.[Hide abstract]
Objective: Fat depots with thermogenic activity have been identified in humans. In mice, the appearance of thermogenic adipocytes within white adipose depots (so-called brown-in-white i.e., brite or beige adipocytes) protects from obesity and insulin resistance. Brite adipocytes may originate from direct conversion of white adipocytes. The purpose of this work was to characterize the metabolism of human brite adipocytes.
Methods: Human multipotent adipose-derived stem cells were differentiated into white adipocytes and then treated with peroxisome proliferator-activated receptor (PPAR)γ or PPARα agonists between day 14 and day 18. Gene expression profiling was determined using DNA microarrays and RT-qPCR. Variations of mRNA levels were confirmed in differentiated human preadipocytes from primary cultures. Fatty acid and glucose metabolism was investigated using radiolabelled tracers, Western blot analyses and assessment of oxygen consumption. Pyruvate dehydrogenase kinase 4 (PDK4) knockdown was achieved using siRNA. In vivo, wild type and PPARa-null mice were treated with a β3-adrenergic receptor agonist (CL316,243) to induce appearance of brite adipocytes in white fat depot. Determination of mRNA and protein levels was performed on inguinal white adipose tissue.
Results: PPAR agonists promote a conversion of white adipocytes into cells displaying a brite molecular pattern. This conversion is associated with transcriptional changes leading to major metabolic adaptations. Fatty acid anabolism i.e., fatty acid esterification into triglycerides, and catabolism i.e., lipolysis and fatty acid oxidation, are increased. Glucose utilization is redirected from oxidation towards glycerol-3-phophate production for triglyceride synthesis. This metabolic shift is dependent on the activation of PDK4 through inactivation of the pyruvate dehydrogenase complex. In vivo, PDK4 expression is markedly induced in wild-type mice in response to CL316,243, while this increase is blunted in PPARα-null mice displaying an impaired britening response.
Conclusions: Conversion of human white fat cells into brite adipocytes results in a major metabolic reprogramming inducing fatty acid anabolic and catabolic pathways. PDK4 redirects glucose from oxidation towards triglyceride synthesis and favors the use of fatty acids as energy source for uncoupling mitochondria.[Hide abstract]
Objective: The role and mechanisms of insulin receptor internalization remain incompletely understood. Previous trafficking studies of insulin receptors involved fluorescent protein tagging at their termini, manipulations that may be expected to result in dysfunctional receptors. Our objective was to determine the trafficking route and molecular mechanisms of functional tagged insulin receptors and endogenous insulin receptors in pancreatic beta-cells.
Methods: We generated functional insulin receptors tagged with pH-resistant fluorescent proteins between domains. Confocal, TIRF and STED imaging revealed a trafficking pattern of inter-domain tagged insulin receptors and endogenous insulin receptors detected with antibodies.
Results: Surprisingly, interdomain-tagged and endogenous insulin receptors in beta-cells bypassed classical Rab5a- or Rab7-mediated endocytic routes. Instead, we found that removal of insulin receptors from the plasma membrane involved tyrosine-phosphorylated caveolin-1, prior to trafficking within flotillin-1-positive structures to lysosomes. Multiple methods of inhibiting caveolin-1 significantly reduced Erk activation in vitro or in vivo, while leaving Akt signaling mostly intact.
Conclusions: We conclude that phosphorylated caveolin-1 plays a role in insulin receptor internalization towards lysosomes through flotillin-1-positive structures and that caveolin-1 helps bias physiological beta-cell insulin signaling towards Erk activation.[Hide abstract]