Obesity-induced tissue alterations resist weight loss: A mechanistic review.

Interventions aimed at weight control often have limited effectiveness in combating obesity. This review explores how obesity-induced dysfunction in white (WAT) and brown adipose tissue (BAT), skeletal muscle, and the brain blunt weight loss, leading to retention of stored fat. In obesity, increased adrenergic stimulation and inflammation downregulate ß-adrenoreceptors and impair catecholaminergic signalling in adipocytes. This disrupts adrenergic-mediated lipolysis, diminishing lipid oxidation in both white and brown adipocytes, lowering thermogenesis and blunting fat loss. Emerging evidence suggests that WAT fibrosis is associated with worse weight loss outcomes; indeed, limiting collagen and laminin-α4 deposition mitigates WAT accumulation, enhances browning, and protects against high-fat-diet-induced obesity. Obesity compromises mitochondrial oxidative capacity and lipid oxidation in skeletal muscle, impairing its ability to switch between glucose and lipid metabolism in response to varying nutrient levels and exercise. This dysfunctional phenotype in muscle is exacerbated in the presence of obesity-associated sarcopenia. Additionally, obesity suppresses sarcolipin-induced sarcoplasmic reticulum calcium ATPase (SERCA) activation, resulting in reduced oxidative capacity, diminished energy expenditure, and increased adiposity. In the hypothalamus, obesity and overnutrition impair insulin and leptin signalling. This blunts central satiety signals, favouring a shift in energy balance toward energy conservation and body fat retention. Moreover, both obese animals and humans demonstrate impaired dopaminergic signalling and diminished responses to nutrient intake in the striatum, which tend to persist after weight loss. This may result in enduring inclinations toward overeating and a sedentary lifestyle. Collectively, the tissue adaptations described pose significant challenges to effectively achieving and sustaining weight loss in obesity.

Muscle-UCP3 in the regulation of energy metabolism.

Uncoupling protein-3 (UCP3) is a mitochondria-regulatory protein with potential energy- homeostatic functions. This study explores the role of UCP3 in the regulation of muscle- and energy metabolism. UCP3 is critical for tuning substrate utilization, favoring lipid oxidation, particularly in conditions of high-fat availability. While UCP3 is non-essential for lipid oxidation during energy excess, it proves vital during fasting, indicating an energy-homeostatic trait. Preliminary evidence indicates UCP3' promotion of glucose uptake and oxidation, at least in conditions of high glucose/low fat availability. However, the dynamics of how fats and glucose differentially influence UCP3 remain undefined. UCP3 exhibits inducible proton transport and uncoupling activity, operating in a dual manner: a resting state with no/low activity and an activated state in the presence of activators. Uncoupling may enhance thermogenesis in specific conditions and in the presence of activators such as fatty acids, thyroid hormones, and catecholamines. This energy-dissipative activity adapts to varying energy availability, balancing energy dissipation with fatty acid oxidation to optimize whole-body energy homeostasis: fasting triggers UCP3 upregulation, enhancing lipid utilization while suppressing uncoupling. Additionally, UCP3 upregulation induces glucose and lipid disposal from the bloodstream and decreases tri-/diglyceride storage in muscle. This process improves mitochondrial functionality and insulin signaling, leading to enhanced systemicgluco-metabolic balance and protection from metabolic conditions. Reviewed evidence suggests that UCP3 plays a crucial role in adapting the system to changing energy conditions. However, the precise role of UCP3 in regulating metabolism requires further elucidation.

Exercise Restores Hypothalamic Health in Obesity by Reshaping the Inflammatory Network.

Obesity and overnutrition induce inflammation, leptin-, and insulin resistance in the hypothalamus. The mediobasal hypothalamus responds to exercise enabling critical adaptions at molecular and cellular level that positively impact local inflammation. This review discusses the positive effect of exercise on obesity-induced hypothalamic dysfunction, highlighting the mechanistic aspects related to the anti-inflammatory effects of exercise. In HFD-fed animals, both acute and chronic moderate-intensity exercise mitigate microgliosis and lower inflammation in the arcuate nucleus (ARC). Notably, this associates with restored leptin sensitivity and lower food intake. Exercise-induced cytokines IL-6 and IL-10 mediate part of these positive effect on the ARC in obese animals. The reduction of obesity-associated pro-inflammatory mediators (e.g., FFAs, TNFα, resistin, and AGEs), and the improvement in the gut-brain axis represent alternative paths through which regular exercise can mitigate hypothalamic inflammation. These findings suggest that the regular practice of exercise can restore a proper functionality in the hypothalamus in obesity. Further analysis investigating the crosstalk muscle-hypothalamus would help toward a deeper comprehension of the subject.

Fine particulate matter induces adipose tissue expansion and weight gain: Pathophysiology.

Dysregulations in energy balance represent a major driver of obesity. Recent evidence suggests that environmental factors also play a pivotal role in inducing weight gain. Chronic exposure to fine particulate matter (PM2.5 ) is associated with white adipose tissue (WAT) expansion in animals and higher rates of obesity in humans. This review discusses metabolic adaptions in central and peripheral tissues that promote energy storage and WAT accumulation in PM2.5 -exposed animals and humans. Chronic PM2.5 exposure produces inflammation and leptin resistance in the hypothalamus, decreasing energy expenditure and increasing food intake. PM2.5 promotes the conversion of brown adipocytes toward the white phenotype, resulting in decreased energy expenditure. The development of inflammation in WAT can stimulate adipogenesis and hampers catecholamine-induced lipolysis. PM2.5 exposure affects the thyroid, reducing the release of thyroxine and tetraiodothyronine. In addition, PM2.5 exposure compromises skeletal muscle fitness by inhibiting Nitric oxide (NO)-dependent microvessel dilation and impairing mitochondrial oxidative capacity, with negative effects on energy expenditure. This evidence suggests that pathological alterations in the hypothalamus, brown adipose tissue, WAT, thyroid, and skeletal muscle can alter energy homeostasis, increasing lipid storage and weight gain in PM2.5 -exposed animals and humans. Further studies will enrich this pathophysiological model.

Nordic Walking Improves Cardiometabolic Parameters, Fitness Performance, and Quality of Life in Older Adults With Type 2 Diabetes.

OBJECTIVE: To assess the effect of Nordic walking (NW) on cardiometabolic health, physical performance, and well-being in sedentary older adults with type 2 diabetes (T2D). METHODS: Fifteen subjects with T2D (female, 5; male, 10; age, 65 ± 6.2 years [mean ± standard deviation]; body mass index, 27.3 ± 4.9 kg/m2 [mean ± standard deviation]) were enrolled in a 6-month NW training program. The fasting glucose and glycosylated hemoglobin levels, lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), systolic blood pressure (SBP), and diastolic blood pressures were measured before and after the intervention. Participants' quality of life (Short-Form Health Survey) and physical fitness (6-minute walking test) were also evaluated. RESULTS: Compared with baseline, NW significantly improved the fasting glucose level (103.5 ± 18.5 vs 168.7 ± 37.7 mg/dL, P = .01), SBP (121.8 ± 12.2 vs 133 ± 14.4 mm Hg, P = .02), physical fitness (759.88 ± 69 vs 615.5 ± 62.6 m, P < .001), and both mental health (54.5 ± 4.4 vs 45.7 ± 5.6, P < .01) and physical health (49.8 ± 4.7 vs 40.3 ± 5.9, P < .01). The levels of glycosylated hemoglobin (6.15% ± 0.8% vs 6.4% ± 1%, P = .46), total cholesterol (162.2 ± 31.2 vs 175.5 ± 28.8 mg/dL, P = .13), low-density lipoprotein cholesterol (95.2 ± 24.2 vs 106.3 ± 32.3 mg/dL, P = .43), and triglycerides (135.5 ± 60.8 vs 127.6 ± 57.4 mg/dL, P = 0.26) improved without reaching significance. CONCLUSION: NW training improved the glycemic levels, SBP, physical fitness, and perception of quality of life in older adults with T2D. NW represents a suitable complementary strategy to improve the global health status in this population.

PM2.5-induced adipose tissue dysfunction can trigger metabolic disturbances.

Exposure to particulate matter ≤2.5 µm in diameter (PM2.5) alters cardiometabolic homeostasis. The reduced oxidative capacity in brown adipocytes and the development of inflammation and insulin resistance in white adipose tissue (WAT) can account for the dysmetabolic setting on PM2.5 exposure. In this forum article, we discuss relevant evidence to highlight a causal connection between PM2.5-induced adipose tissue dysfunction and cardiometabolic disturbances.

White and brown adipose tissue functionality is impaired by fine particulate matter (PM2.5) exposure.

Chronic exposure to high levels of particulate matter (PM) is correlated to a higher prevalence of cardio-metabolic disturbances. Adipose tissue represents a pivotal regulator of metabolic homeostasis, and its dysfunction is associated with health issues in PM-exposed models. This review discusses the adaptive changes of white (WAT) and brown (BAT) adipose tissue in response to fine particulate matter (PM2.5), investigating the underlying pathophysiology. In exposed models, PM2.5 increases oxidative stress and impairs mitochondria functionality and biogenesis in WAT and BAT. Chronic exposure also upregulates the main apoptotic/pro-inflammatory pathways and promotes the infiltration of monocytes and the accumulation of activated macrophages. Oxidative stress and inflammation are responsible for the inhibition of insulin signal transduction and glucose uptake in both the adipose tissues. The increased inflammatory status also suppresses the metabolic activity of brown adipocytes, promoting the whitening. Altogether, this evidence suggests the shift of WAT and BAT toward an inflammatory and metabolic dysfunctional phenotype. Although the underlying mechanisms remain to be clarified, the development of inflammation in lungs, gut, and hypothalamus seems to have a pivotal role in the alteration of adipose tissue homeostasis. The potential consequences on systemic cardio-metabolic health render the relationship PM-adipose tissue a key issue to investigate.

Exercise tolls the bell for key mediators of low-grade inflammation in dysmetabolic conditions.

Metabolic conditions share a common low-grade inflammatory milieu, which represents a key-factor for their ignition and maintenance. Exercise is instrumental for warranting systemic cardio-metabolic balance, owing to its regulatory effect on inflammation. This review explores the effect of physical activity in the modulation of sub-inflammatory framework characterizing dysmetabolic conditions. Regular exercise suppresses plasma levels of TNFα, IL-1ß, FFAs and MCP-1, in dysmetabolic subjects. In addition, a single session of training increases the anti-inflammatory IL-10, IL-1 receptor antagonist (IL-1ra), and muscle-derived IL-6, mitigating low-grade inflammation. Resting IL-6 levels are decreased in trained-dysmetabolic subjects, compared to sedentary. On the other hand, the acute release of muscle-IL-6, after exercise, seems to exert a regulatory effect on the metabolic and inflammatory balance. In fact, muscle-released IL-6 is presumably implicated in fat loss and boosts plasma levels of IL-10 and IL-1ra. The improvement of adipose tissue functionality, following regular exercise, is also critical for the mitigation of sub-inflammation. This effect is likely mediated by muscle-released IL-15 and IL-6 and partly relies on the brown-shifting of white adipocytes, induced by exercise. In obese-dysmetabolic subjects, moderate training is shown to restore gut-microbiota health, and this mitigates the translocation of bacterial-LPS into bloodstream. Finally, regular exercise can lower plasma advanced glycated endproducts. The articulated physiology of circulating mediators and the modulating effect of the pathophysiological background, render the comprehension of the exercise-regulatory effect on sub-inflammation a key issue, in dysmetabolism.

Physical activity as a proxy to ameliorate inflammation in patients with type 2 diabetes and periodontal disease at high cardiovascular risk.

While the beneficial impact of physical activity has been ascertained in a variety of pathological scenarios, including diabetes and low-grade systemic inflammation, its potential remains still putative for periodontal health. Periodontal disease has been associated with inflammatory systemic alterations, which share a common denominator with type 2 diabetes mellitus and cardiovascular disease. Physical exercise, along with nutritional counseling, is a cornerstone in the treatment and prevention of type 2 diabetes, also able to reduce the prevalence of periodontal disease and cardiovascular risk. In addition, considering the higher incidence of periodontitis in patients with type 2 diabetes compared to healthy controls, the fascinating research question would be whether physical activity could relieve the inflammatory pressure exerted by the combination of these two diseases. This multi-disciplinary viewpoint discusses available literature in order to argument the hypothesis of a "three-way relationship" linking diabetes, periodontitis, and physical activity.

Partial-Body Cryostimulation Increases Resting Energy Expenditure in Lean and Obese Women.

Cryostimulation is currently seen as a potential adjuvant strategy to tackle obesity and dysmetabolism by triggering cold-induced thermogenesis. Although suggestive, the underlying mechanisms are still poorly elucidated. We tested whether single or repeated applications of partial-body cryostimulation (PBC) could influence resting energy expenditure (REE) in exposed individuals. Fifteen middle-aged obese and sixteen control lean women (body mass index 31 ± 1.6 kg/m2 and 22 ± 1.7 kg/m2) underwent a daily PBC (-130 °C × 150 s) for five consecutive days. Resting energy metabolism (REE) was assessed by indirect calorimetry pre- and post-PBC on day 1 and day 5. As concerns REE, the linear mixed model revealed that REE changes were explained by session and time (F1,29 = 5.58; p = 0.02; ƞp2 = 0.16) independent of the group (F1,29 = 2.9; p = 0.09; ƞp2 = 0.09). REE pre-PBC increased from day 1 to day 5 either in leans (by 8.2%, from 1538 ± 111 to 1665 ± 106 kcal/day) or in obese women (by 5.5%, from 1610 ± 110 to 1698 ± 142 vs kcal/day). Respiratory quotient was significantly affected by the time (F1,29 = 51.61; p < 0.000001, ƞp2 = 0.64), as it increased from pre- to post-PBC, suggesting a shift in substrate oxidation. According to these preliminary data, cold-induced thermogenesis could be explored as a strategy to elevate REE in obese subjects. Longitudinal studies could test whether chronic PBC effects may entail favorable metabolic adaptations.

Potential role of microRNAs in the regulation of adipocytes liposecretion and adipose tissue physiology.

Adipose tissue is a dynamic endocrine organ playing a pivotal role in metabolism modulation. Adipocytes differentiation requires a highly orchestrated series of changes of gene expression in precursor cells. At the same time, white mature adipocytes are plastic cells able to reversibly transdifferentiate toward fibroblast-like cells via the liposecretion process, returning back to a non-committed status of the cells. In particular, adipose tissue microenvironment along with external signaling molecules such as adipokines, cytokines and growth factors can regulate adipocytes physiology through complex molecular networks. MicroRNAs (miRNAs), a type of non-coding RNA, acting as fine regulators of biological processes and their expression is sensible to the environment and cellular status changes. MiRNAs are thought to play a pivotal role in regulating the physiology of adipose tissue as well as in the development of obesity and associated metabolic disturbances, although the underlying mechanisms have not been identified so far. Elucidating the molecular mechanisms orchestrating adipose tissue biology is required to better characterize obesity and its associated diseases. In this respect, the review aims to analyze the microRNAs potentially involved in adipogenesis highlighting their role in the process of liposecretion, adipocyte proliferation, and adipokines secretion. The role of microRNAs in the development of obesity and obesity-associated disorders is also discussed.

iPSC-derived familial Alzheimer's PSEN2 N141I cholinergic neurons exhibit mutation-dependent molecular pathology corrected by insulin signaling.

BACKGROUND: Type 2 diabetes (T2D) is a recognized risk factor for the development of cognitive impairment (CI) and/or dementia, although the exact nature of the molecular pathology of T2D-associated CI remains obscure. One link between T2D and CI might involve decreased insulin signaling in brain and/or neurons in either animal or postmortem human brains as has been reported as a feature of Alzheimer's disease (AD). Here we asked if neuronal insulin resistance is a cell autonomous phenomenon in a familial form of AD. METHODS: We have applied a newly developed protocol for deriving human basal forebrain cholinergic neurons (BFCN) from skin fibroblasts via induced pluripotent stem cell (iPSC) technology. We generated wildtype and familial AD mutant PSEN2 N141I (presenilin 2) BFCNs and assessed if insulin signaling, insulin regulation of the major AD proteins Aß and/or tau, and/or calcium fluxes is altered by the PSEN2 N141I mutation. RESULTS: We report herein that wildtype, PSEN2 N141I and CRISPR/Cas9-corrected iPSC-derived BFCNs (and their precursors) show indistinguishable insulin signaling profiles as determined by the phosphorylation of canonical insulin signaling pathway molecules. Chronic insulin treatment of BFCNs of all genotypes led to a reduction in the Aß42/40 ratio. Unexpectedly, we found a CRISPR/Cas9-correctable effect of PSEN2 N141I on calcium flux, which could be prevented by chronic exposure of BFCNs to insulin. CONCLUSIONS: Our studies indicate that the familial AD mutation PSEN2 N141I does not induce neuronal insulin resistance in a cell autonomous fashion. The ability of insulin to correct calcium fluxes and to lower Aß42/40 ratio suggests that insulin acts to oppose an AD-pathophysiology. Hence, our results are consistent with a potential physiological role for insulin as a mediator of resilience by counteracting specific metabolic and molecular features of AD.

Insulin Sensitivity and Glucose Homeostasis Can Be Influenced by Metabolic Acid Load.

Recent epidemiological findings suggest that high levels of dietary acid load can affect insulin sensitivity and glucose metabolism. Consumption of high protein diets results in the over-production of metabolic acids which has been associated with the development of chronic metabolic disturbances. Mild metabolic acidosis has been shown to impair peripheral insulin action and several epidemiological findings suggest that metabolic acid load markers are associated with insulin resistance and impaired glycemic control through an interference intracellular insulin signaling pathways and translocation. In addition, higher incidence of diabetes, insulin resistance, or impaired glucose control have been found in subjects with elevated metabolic acid load markers. Hence, lowering dietary acid load may be relevant for improving glucose homeostasis and prevention of type 2 diabetes development on a long-term basis. However, limitations related to patient acid load estimation, nutritional determinants, and metabolic status considerably flaws available findings, and the lack of solid data on the background physiopathology contributes to the questionability of results. Furthermore, evidence from interventional studies is very limited and the trials carried out report no beneficial results following alkali supplementation. Available literature suggests that poor acid load control may contribute to impaired insulin sensitivity and glucose homeostasis, but it is not sufficiently supportive to fully elucidate the issue and additional well-designed studies are clearly needed.

Adipocytes properties and crosstalk with immune system in obesity-related inflammation.

Obesity is a condition likely associated with several dysmetabolic conditions or worsening of cardiovascular and other chronic disturbances. A key role in this mechanism seem to be played by the onset of low-grade systemic inflammation, highlighting the importance of the interplay between adipocytes and immune system cells. Adipocytes express a complex and highly adaptive biological profile being capable to selectively activate different metabolic pathways in order to respond to environmental stimuli. It has been demonstrated how adipocytes, under appropriate stimulation, can easily differentiate and de-differentiate thereby converting themselves into different phenotypes according to metabolic necessities. Although underlying mechanisms are not fully understood, growing in adipocyte size and the inability of storing triglycerides under overfeeding conditions seem to be crucial for the switching to a dysfunctional metabolic profile, which is characterized by inflammatory and apoptotic pathways activation, and by the shifting to pro-inflammatory adipokines secretion. In obesity, changes in adipokines secretion along with adipocyte deregulation and fatty acids release into circulation contribute to maintain immune cells activation as well as their infiltration into regulatory organs. Over the well-established role of macrophages, recent findings suggest the involvement of new classes of immune cells such as T regulatory lymphocytes and neutrophils in the development inflammation and multi systemic worsening. Deeply understanding the pathways of adipocyte regulation and the de-differentiation process could be extremely useful for developing novel strategies aimed at curbing obesity-related inflammation and related metabolic disorders.

Key-genes regulating the liposecretion process of mature adipocytes.

White mature adipocytes (MAs) are plastic cells able to reversibly transdifferentiate toward fibroblast-like cells maintaining stem cell gene signatures. The main morphologic aspect of this transdifferentiation process, called liposecretion, is the secretion of large lipid droplets and the development of organelles necessary for exocrine secretion. There is a considerable interest in the adipocyte plastic properties involving liposecretion process, but the molecular details are incompletely explored. This review analyzes the gene expression of MAs isolated from human subcutaneous fat tissue with respect to bone marrow (BM)-derived mesenchymal stem cells (MSC) focusing on gene regulatory pathways involved into cellular morphology changes, cellular proliferation and transports of molecules through the membrane, suggesting potential ways to guide liposecretion. In particular, Wnt, MAPK/ERK, and AKT pathways were accurately described, studying up- and down-stream molecules involved. Moreover, adipogenic extra- and intra-cellular interactions were analyzed studying the role of CDH2, CDH11, ITGA5, E-Syt1, PAI-1, IGF1, and INHBB genes. Additionally, PLIN1 and PLIN2 could be key-genes of liposecretion process regulating molecules transport through the membrane. All together data demonstrated that liposecretion is regulated through a complex molecular networks that are able to respond to microenvironment signals, cytokines, and growth factors. Autocrine as well as external signaling molecules might activate liposecretion affecting adipocytes physiology.

Enriching Diet with n-3 PUFAs to Help Prevent Cardiovascular Diseases in Healthy Adults: Results from Clinical Trials.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are believed to be important for cardiovascular health. Many investigations have been carried out in an attempt to examine the effect of n-3 PUFAs intake, in the form of supplementation or fortified foods, for the management of cardiovascular disease (CVD) and risk factors for CVD, whereas less is known about the effect on healthy individuals. The present study reviews the available literature in order to examine the relationship between n-3 PUFAs intake, either via supplementation or enriched food, and the prevention of CVD among healthy adults. Interventional clinical trials on subjects aged >18 years old with none of the established risk factors for CVD have been considered for review. n-3 PUFAs supplementation or enriched food may positively regulate triglycerides and some lipoprotein subsets, as well as several vascular and coagulation parameters, even in healthy patients, presenting no risk factors for CVD, suggesting a protective effect. Diet enrichment with omega-3 is likely to be useful in helping to lower the risk of developing CVD in healthy individuals, but still offers no strong evidence of a tangible benefit on a population level. Additional studies are needed to determine the optimal daily intake, especially to prevent the unfavorable effects of PUFAs over-consumption.

Diet-induced acidosis and alkali supplementation.

Western diet, high in protein-rich foods and poor in vegetables, is likely to be responsible for the development of a moderate acid excess leading to metabolism deregulation and the onset or worsening of chronic disturbances. Available findings seem to suggest that diets with high protein/vegetables ratio are likely to induce the development of calcium lithiasis, especially in predisposed subjects. Moreover, some evidence supports the hypothesis of bone metabolism worsening and enhanced bone loss following acid-genic diet consumption although available literature seems to lack direct and conclusive evidence demonstrating pathological bone loss. According to other evidences, diet-induced acidosis is likely to induce or accelerate muscle wasting or sarcopenia, especially among elderlies. Furthermore, recent epidemiological findings highlight a specific role of dietary acid load in glucose metabolism deregulation and insulin resistance. The aim of this review is to investigate the role of acid-genic diets in the development of the mentioned metabolic disorders focusing on the possible clinical improvements exerted by alkali supplementation.