The current obesity epidemic poses a major public health issue since obesity predisposes towards several chronic diseases BMI and total adiposity are positively correlated with cardiometabolic disease risk at the population level However, body fat distribution and an impaired adipose tissue function, rather than total fat mass, better predict insulin resistance and related complications at the individual level Adipose tissue dysfunction is determined by an impaired adipose tissue expandability, adipocyte hypertrophy, altered lipid metabolism, and local inflammation Recent human studies suggest that adipose tissue oxygenation may be a key factor herein A subgroup of obese individuals - the 'metabolically healthy obese' (MHO) - have a better adipose tissue function, less ectopic fat storage, and are more insulin sensitive than obese metabolically unhealthy persons, emphasizing the central role of adipose tissue function in metabolic health However, controversy has surrounded the idea that metabolically healthy obesity may be considered really healthy since MHO individuals are at increased (cardio)metabolic disease risk and may have a lower quality of life than normal weight subjects due to other comorbidities Detailed metabolic phenotyping of obese persons will be invaluable in understanding the pathophysiology of metabolic disturbances, and is needed to identify high-risk individuals or subgroups, thereby paving the way for optimization of prevention and treatment strategies to combat cardiometabolic diseases

/pdf/the-metabolic-phenotype-in-obesity-fat-mass-body-fat-1f28h51lv5.pdf

The Metabolic Phenotype in Obesity: Fat Mass, Body Fat Distribution, and Adipose Tissue Function

Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease.

Type 2 diabetes as an inflammatory disease.

To fulfill its role as the major energy-storing tissue, adipose has several unique properties that cannot be seen in any other organ, including an almost unlimited capacity to expand in a non-transformed state. As such, the tissue requires potent mechanisms to remodel, acutely and chronically. Adipocytes can rapidly reach the diffusional limit of oxygen during growth; hypoxia is therefore an early determinant that limits healthy expansion. Proper expansion requires a highly coordinated response among many different cell types, including endothelial precursor cells, immune cells, and preadipocytes. There are therefore remarkable similarities between adipose expansion and growth of solid tumors, a phenomenon that presents both an opportunity and a challenge, since pharmacological interventions supporting healthy adipose tissue adaptation can also facilitate tumor growth.

/pdf/adipose-tissue-remodeling-and-obesity-4giwx42hfm.pdf

Adipose tissue remodeling and obesity

The rise in the incidence of obesity has led to a major interest in the biology of white adipose tissue. The tissue is a major endocrine and signaling organ, with adipocytes, the characteristic cel...

Hypoxia and Adipose Tissue Function and Dysfunction in Obesity

Obesity is one of the major health burdens of the 21st century as it contributes to the growing prevalence of its related comorbidities, including insulin resistance and type 2 diabetes. Growing evidence suggests a critical role for overnutrition in the development of low-grade inflammation. Specifically, chronic inflammation in adipose tissue is considered a crucial risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. The triggers for adipose tissue inflammation are still poorly defined. However, obesity-induced adipose tissue expansion provides a plethora of intrinsic signals (e.g., adipocyte death, hypoxia, and mechanical stress) capable of initiating the inflammatory response. Immune dysregulation in adipose tissue of obese subjects results in a chronic low-grade inflammation characterized by increased infiltration and activation of innate and adaptive immune cells. Macrophages are the most abundant innate immune cells infiltrating and accumulating into adipose tissue of obese individuals; they constitute up to 40% of all adipose tissue cells in obesity. In obesity, adipose tissue macrophages are polarized into pro-inflammatory M1 macrophages and secrete many pro-inflammatory cytokines capable of impairing insulin signaling, therefore promoting the progression of insulin resistance. Besides macrophages, many other immune cells (e.g., dendritic cells, mast cells, neutrophils, B cells, and T cells) reside in adipose tissue during obesity, playing a key role in the development of adipose tissue inflammation and insulin resistance. The association of obesity, adipose tissue inflammation, and metabolic diseases makes inflammatory pathways an appealing target for the treatment of obesity-related metabolic complications. In this review, we summarize the molecular mechanisms responsible for the obesity-induced adipose tissue inflammation and progression toward obesity-associated comorbidities and highlight the current therapeutic strategies.

/pdf/chronic-adipose-tissue-inflammation-linking-obesity-to-38oos0cd7h.pdf

Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes.

Recent studies suggest that adipose tissue hypoxia (ATH) may contribute to endocrine dysfunction in adipose tissue of obese mice. In this study, we examined hypoxia's effects on metabolism in adipo...

https://www.physiology.org/doi/pdf/10.1152/ajpendo.90760.2008

Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue

Background: Glucose homeostasis relies on insulin to suppress hepatic glu-cose production and to stimulate glucose uptake by peripheral tissues (pri-marily skeletal muscle) during and after a meal or glucose load. Glucosemetabolism impairments in the liver and⁄or muscle attenuate these insulinactions, causing hyperglycemia. Thus, identifying the loci of the impair-ments can improve the understanding of hyperglycemia and enable organ-targeted interventions.Methods: Studies were performed to identify such loci using modiﬁed oralglucose tolerance test (OGTT) techniques in individuals with type 2 diabe-tes (T2D) and overweight⁄obese individuals.Results: Individuals with severe T2D were found to have signiﬁcantlyimpaired glucose metabolism in both the liver and muscle. In contrast,impairments in glucose metabolism in individuals with non-severe T2Dwere predominantly localized in the liver or muscle, but not both. Simi-larly, milder impairments in overweight or obese individuals were clearlylocalized in either the liver or muscle, but not both. All these impairmentsare quantiﬁable.Conclusion: Impairments in glucose metabolism in the liver and muscle canbe differentiated and quantiﬁed in a clinical setting.Keywords: hyperglycemia, localization, organ impairment, type 2 diabetes.Signiﬁcant ﬁndings of the study: The liver or muscle as the main source of hyperglycemia varies from personto person and can be diagnosed individually to enable personalized glycemic control.What this study adds: An improved understanding of the mechanism underlying postprandial hyperglycemiaat the organ level and the possibility of selectively targeting the liver or muscle in the intervention and pre-vention of type 2 diabetes.

Locating the source of hyperglycemia: liver versus muscle.

BACKGROUND Dipeptidyl peptidase-IV (DPP-4) inhibitors are now used to improve postprandial glycemic control in type 2 diabetes. However, their effects on hepatic glucose production (HGP) in obesity are not clear. This study was designed to test the hypothesis that gluconeogenesis and HGP can be modulated by DPP-4 inhibitors in obesity. METHODS Sprague Dawley male rats were divided into four groups, each on a different diet: general rat chow, n = 10 (G); G + sitagliptin, n = 10; high fat chow (obesity), n = 10 (55% fat calories, HFO); HFO + sitagliptin, n = 10. After 10 weeks, the rats were fasted overnight and glucose metabolism was determined using 3-(3)H-glucose and (14)C-glycerol as tracers. RESULTS Glycerol rate of appearance (P 0.05). Gluconeogenesis in HFO group was five times of that in G rats (P < 0.01), but was significantly declined in HFO + sitagliptin group (P < 0.0001). CONCLUSIONS Gluconeogenesis and HGP were inhibited by sitagliptin in high fat-induced obese rats due to decreased glycerol availability, which was a result of reduced glycerol release from adipose tissues. The finding suggests that sitagliptin is potentially useful for controlling fasting glucose in obesity, thereby delaying or preventing the development of diabetes.

Decreased hepatic glucose production in obese rats by dipeptidyl peptidase-IV inhibitor sitagliptin.

Ren et al. recently reported an elegant study of measuring lipid contents of human muscle in vivo using proton magnetic resonance spectroscopy (MRS) techniques (1). The intramyocellular (IMCL) and extramyocellular lipid proton resonances appear as two almost completely resolved peaks for both the methylene and methyl groups of the acyl chains. The methyl resonance peak is used for the quantification of IMCL, in absolute terms. This allows direct comparisons with the results in the literature that are mostly in the absolute terms. The technical advancements shall facilitate the noninvasive investigation of muscle lipids that has been very active for nearly two decades since the initial application by Schick et al. (2).

In the report, the authors equated IMCL to IMCL triglycerides (imcTG). This is worth discussion. As MRS quantifies lipids based on the amounts of methylene or methyl protons, the results should reflect TG and phospholipids as well as other fatty acid-containing lipids (3). Cytosolic lipids also include diglycerides, acylcarnitines, and nonesterified fatty acids at substantial levels, especially the latter, with distinct functions (4,5). Lactate methyl resonance peak also overlaps with the lipid methylene resonance (6,7). To measure TG, it is sometimes assumed that cellular phospholipids produce broad peaks that are lost in the background (8). However, no specific tests seem to have been done in this regard to erase the concern and ensure that the resonances are largely free of interference from non-TG lipids. In fact, in most MRS studies this concern is not explicitly addressed. Therefore, it is uncertain whether these resonances can be attributed to imcTG. For this reason, the term IMCL seems more appropriate. However, this term is confused with imcTG in that IMCL is usually studied either as an energy source during exercise (9,10) or as a factor related to insulin resistance (11,12), to which only is imcTG relevant. After more than a decade of such “acclimation,” IMCL seems to have been construed to be almost synonymous with imcTG.

Cellular phospholipids are often more abundant than imcTG, a small lipid pool as local energy source (13). In addition to plasma membrane phospholipids, some intracellular phospholipids are in close proximity to or in direct contact with imcTG droplets such as those of mitochondrial membrane as shown by electron microscope (14). Therefore, it seems logical to speculate that MRS may over-estimate imcTG by including non-TG lipids. For instance, IMCL concentration has been reported to be as high as 1.76–2.2% ± 1.1% (IMCL protons as % of water protons) for soleus muscle of obese and healthy lean humans, respectively (15,16). This translates into a TG concentration of 29.3 mmol/kg wet weight after taking into account the differences in the number of protons (62 vs. 2, Ref. 17) and molecular weight of TG (assuming 750) and water molecules, and assuming a muscle water content of 76% (Ref. 18). This is nearly four times higher than the imcTG concentration measured biochemically at 2.1–2.7 mmol/kg wet weight in vastus lateralis of normal and healthy lean humans, (19,20), even after taking into consideration the difference in imcTG concentration between soleus and vastus lateralis (assuming 3:1). There are higher values of imcTG measured biochemically but they are likely contaminated by adipocytes (21). For this reason, we place more confidence on the lower values achieved by using careful dissection techniques (22). Nonetheless, IMCL of soleus and tibialis anterior reported by Ren et al. (1,23) are in the expected range. However, IMCL reported for quadriceps or gastrocnemius are often overestimates (23,24). Interestingly, Howald et al. reported underestimation of tibialis anterior lipids by MRS (14). Although their MRS result is in the expected range for this less oxidative muscle, the results from biochemical and electron microscope (EM) measurements (6.5 and 5.9 mmol/kg ww, respectively) for the same muscle are unrealistically as high as that for oxidative soleus muscle. Therefore, an underestimation by MRS could not be established. It is not clear what caused these overestimations. In particular, it is not known whether non-TG lipids contributed to the methylene and methyl resonances based on which IMCL is quantified. After nearly two decades of active use of the MRS technique, this fundamental question remains unclear. As MRS increasingly becomes a major research tool in the investigation of tissue lipid metabolism, clarifying this issue is critical to better understand the quantitative relation-ship between IMCL and imcTG so that informed comparisons can be made between them. The significance and usefulness of MRS technology to the studies of tissue lipids as related to insulin resistance and sports medicine will depend on the extent that it can reliably probe the relevant lipid pools.

Intramyocellular lipids versus intramyocellular triglycerides.

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Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue

Locating the source of hyperglycemia: liver versus muscle.

Decreased hepatic glucose production in obese rats by dipeptidyl peptidase-IV inhibitor sitagliptin.

Intramyocellular lipids versus intramyocellular triglycerides.