Adiposopathy Research Articles

Sick fat (adiposopathy) as the main contributor to metabolic syndrome

Obesity, primarily the accumulation of visceral fat (prone to lipolysis and inflammation) is considered the most important pathogenetic link in insulin resistance, metabolic syndrome and type 2 diabetes mellitus. The purpose of the review was to present and summarize current information on the negative impact of adipose tissue dysfunction and the role of this phenomenon in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus. Material and methods. A systematic search of Web of Science, EMBASE, MEDLINE, and Google Scholar databases was performed. Results. Adipose tissue secretes a huge variety of biologically active substances - free fatty acids, adipokines, inflammatory mediators. These substances have a negative effect on insulin-sensitive and all other tissues, inducing inextricably linked freeradical oxidation, mitochondrial dysfunction, histotoxic hypoxia, maladaptive autophagy, apoptosis, dysregulation of transcriptome and post-translational processes, overload of non-fat tissues with lipids (lipotoxicity) enhanced by hyperinsulinemia, and many other cytotoxic mechanisms. Target organ damage disrupts the finely tuned network of feedbacks between the brain, liver, gut, microbiome, muscles, adipose tissue, classic glands and the rest of the organs, provided by myokines, hepatokines, bathokines and other substances, among others. Based on some experimental and clinical data, we agree with the notions that the qualitative aspect - adipocyte dysfunction (adiposopathy) - is at least as important as cell mass. Sick fat has a number of differences from healthy tissue, among which there are indicated mitochondrial dysfunction, inflammation, disorders of browning, cell death, and removal of senescent cells (senolysis). The obesity paradox can be explained from the pathophysiological point of view by this distinction (although the main explanation, in our opinion, should be sought in the internal validity of the works revealing this phenomenon). Conclusion. The treatment of obesity and its consequences should be based on «healing» rather than «extermination» of adipocytes. Implementation of this approach requires homeostatic influence on neuroimmunoendocrine regulation. Of the available tools, metformin, incretin drugs, sodium-glucose transporter inhibitors, and bariatric surgery probably meet this requirement the most.

Whole transcriptome RNA-seq reveals key regulatory factors involved in type 2 diabetes pathology in peripheral fat of Asian Indians

The prevalence of Type 2 Diabetes has reached an epidemic proportion particularly in south Asian countries. We have earlier shown that the anatomical fat distribution, termed ‘thin fat phenotype’ in this population indeed plays a major role for their T2D-predisposition it is indeed the sick fat or adiposopathy, which is the root cause of metabolic syndrome and diabetes and affects both—peripheral, as well as visceral adipose tissue compartments. In present study, we have attempted to unravel the altered regulatory mechanisms at the level of transcription factors, and miRNAs those may likely accounts to T2D pathophysiology in femoral subcutaneous adipose tissue. We prioritized transcription factors and protein kinases as likely upstream regulators of obtained differentially expressed genes in this RNA-seq study. An inferred network of these upstream regulators was then derived and the role of TFs and miRNAs in T2D pathophysiology was explored. In conclusions, this RNS-Seq study finds that peripheral subcutaneous adipose tissue among Asian Indians show pathology characterized by altered lipid, glucose and protein metabolism, adipogenesis defect and inflammation. A network of regulatory transcription factors, protein kinases and microRNAs have been imputed which converge on the process of adipogenesis. As the majority of these genes also showed altered expression in diabetics and some of them are also circulatory, therefore they deserve further investigation for potential clinical diagnostic and therapeutic applications.

Diabetes and Insulin Resistance Show Association With Femoral Instead of Abdominal Adipocyte Size in Asian Indians

Objectives: Energy intake exceeding expenditure results in adipogenesis, which consists of adipocyte hyperplasia and hypertrophy. Adipocyte hypertrophy is the pathological hallmark of ‘sick fat’ responsible for the development of insulin resistance and diabetes mellitus. In Asian Indians, who show a thin, fat phenotype, the association of adipocyte hypertrophy in various fat depots with insulin resistance and diabetes is not precisely known. The objective of this study is to find an association between adipocyte size of abdominal and thigh fat depot and certain parameters of diabetes mellitus. Material & Methods: In this cross-sectional analytical study, 172 patients were recruited. Abdominal subcutaneous and visceral fat samples were available of 100 patients (Non-diabetics: 56; Diabetics: 44), whereas thigh fat was analyzed in 72 patients (Non-diabetics: 40; Diabetics: 32). All participants had a BMI of less than 30 kg/m2 to negate the effect of obesity on adipocyte size. Fasting glucose, insulin, HbA1c, lipid profile including triglycerides, and total cholesterol were measured in all participants, and HOMA-IR was calculated. Adipocyte size in biopsied tissue after fixation was measured with the help of Motic Panthera Moticam 5 trinocular microscope (BA210LED) and Adobe Photoshop CC image analysis tool. Results: Mean adipocyte size in abdominal visceral compartment in diabetics and non-diabetics were 16610.3 ± 889.5 um2 and 16129.8 ± 878.5 um2 respectively. Whereas, mean adipocyte size in abdominal subcutaneous fat in diabetics and non-diabetics were 15071.0 ± 1261.1 um2 and 14356.8 ± 1004.7 um2 respectively. Adipocyte size difference of both the abdominal compartments between diabetic and non-diabetic group was statistically non-significant (p= 0.70 & 0.65 in omental and abdominal subcutaneous compartments respectively). Mean adipocyte size of thigh in diabetics and non-diabetics were 13070.2 ± 1416.2 um2 and 9020.1 ± 811.1 um2 respectively and difference between adipocyte size between both groups was statistically significant (p = 0.01). Thigh Adipocyte size in diabetic subgroup was positively correlated with HOMA -IR (r = 0.4, p = 0.02), triglycerides (r= 0.4, p = 0.03), waist circumference (r = 0.32, p = 0.03). On multivariate linear regression analysis HOMA-IR (β= 0.45, p=0.00), triglycerides (β=0.38, p=0.01) and waist circumference (β=0.35, p=0.02) are predictor of increased adipocyte size. Conclusion: We found that thigh adipocyte size was significantly larger in diabetics in comparison to non-diabetics, whereas no such difference was found in the abdominal fat compartment. In diabetic patients’ thigh, adipocyte size was positively correlated with HOMA-IR, waist circumference, and triglyceride levels, underlining the role of peripheral fat depots in the pathogenesis of diabetes type 2.

Adiposopathy: The Role of “Sick Fat” in Cardiovascular Diseases and Exercise Mediated Improvement in Adipose Tissue Function

Adiposopathy: The Role of “Sick Fat” in Cardiovascular Diseases and Exercise Mediated Improvement in Adipose Tissue Function

CONCEPTUAL STUDY OF ADIPOSOPATHY WITH REFERENCE OF LANGHAN UPAKRAMA FOR HEALTHY LIFE

Lifestyle in modern era delivers a lot of stress and due to extreme use of Guru (heavy), Madhura (sweet), Snigdha (oily), Shita (cold) Ahar and Vihar like Alashya (stationary), Adhyasana (taking another food before undigested food), Vishamashan (different timing of food) etc, people get suffer with a disease like excessive body fat or sick fat or adiposopathy. Adiposopathy leads to several metabolic diseases. Langhana upakrama (fasting) will be an effective treatment in adiposopathy. Several studies by researchers, assembled to check anatomical and pathophysiological abnormalities of adiposopathy and review of different aspects of Langhana upakrama in Samhita in perspective of metabolic disorders especially due to adiposopathy. Data study shows that on positive energy intake, accumulated subcutaneous adipose tissue, visceral adipose tissue and other fat depots can be pathogenic. This pathogenic adipose tissue causes many metabolic diseases like obesity, type 2 diabetes, hypertension, hypothyroidism, liver diseases etc. By the studies of different Samhita we can articulate that Langhana upakrama is able to bring lightness and thinness to body. Finally we can conclude that by the Langhana upakrama body uses all types of sick fat from all fat depots and it can reverse the process of adiposopathy and body becomes healthy.

Granzyme B Expression in Visceral Adipose Tissue Associates With Local Inflammation and Glyco-Metabolic Alterations in Obesity.

Granzyme B (GrB) is a serine protease produced by immune and non-immune cells, able to promote multiple processes, like apoptosis, inflammation, extracellular matrix remodeling and fibrosis. GrB expression in visceral adipose tissue (VAT) was associated with tissue damage, local inflammation and insulin resistance in obesity murine model, but there is no data in humans. Aim of this study was to explore the expression of GrB in VAT from obese subjects in relation to adipose tissue injury, inflammation, metabolic alterations and GrB circulating levels. For this purpose, 85 obese individuals undergoing bariatric surgery and 35 healthy subjects (as control) were recruited at Sapienza University, Rome, Italy. Study participants underwent clinical work-up and routine biochemistry. mRNA expression of GrB in VAT and of a panel of VAT inflammatory markers was analyzed by real-time PCR. Serum GrB levels were measured by Elisa Affymetrix EBIO. We observed that 80% of obese patients expressed GrB mRNA in VAT, and GrB VAT expression was associated with the presence of local inflammation and glucose homeostasis alterations. Moreover, GrB serum levels, which were higher in obese subjects compared to non-obese healthy individuals, were associated with GrB expression in VAT and glyco-metabolic impairment. Our data show, for the first time in humans, that obese subjects with “sick” fat and altered glucose tolerance exhibit GrB expression in VAT, and suggest that GrB might contribute to obesity-related VAT inflammatory remodeling and glucose homeostasis dysregulation. Moreover, increased circulating GrB levels might represent a possible peripheral marker of VAT dysfunction in metabolic diseases.

Obesity and Body Composition in Man and Woman: Associated Diseases and the New Role of Gut Microbiota.

Obesity is now recognized as a worldwide health issue and has reached epidemic proportions, affecting both developed and developing countries. The World Obesity Federation stated that "Obesity is a chronic relapsing disease process": as a result, obesity has been recognized internationally as a chronic disease. The primary cause of the metabolic syndrome and increase of the cardiovascular risk have been identified in "sick fat", a condition then defined as adiposopathy. Heart attacks, strokes and renal failures are pathologies that have mid-risk factors such as dyslipidemia, hypertension and diabetes, which in turn are caused by obesity, whose primary risk factor is represented by the diet. The aim of the present review is to consider the importance of body composition, together with chronic inflammation and a new gut microbiota data that may turn out to be crucial elements of some target treatment of human obesity. In this review, we performed research using PubMed database reviewing the evidence in the literature of evidence information regarding the link between obesity and body composition in the development of metabolic disease via inflammation markers and in particular, the new role exerted by gut microbiota. Several papers were evaluated searching for differences in fat mass and disease risk. We also identified the same papers dealing with differences in body composition and metabolic syndrome. Our attention focuses also on a new frontier of gut microbiota composition in the body weight decrease and anti-inflammatory effects. To the saving of lean mass, for the prevention of cardiometabolic diseases, also considering the relationship with obesity, it is necessary to reduce the inflammatory state, acting on the gut-microbiota and on the intestinal permeability. To improve the health of the intestinal flora, we propose a 4P medicine and treatment with probiotics, prebiotics, postbiotics, and polyphenols.

Sick fat: the good and the bad of old and new circulating markers of adipose tissue inflammation.

Adipose tissue (AT)is one of the largest endocrine organs contributing to metabolic homeostasis. The functional pleiotropism ofAT depends on its ability to secrete a large number of hormones, cytokines, extracellular matrix proteins and growth factors, all influencing many local and systemic physiological and pathophysiological processes. In condition of chronic positive energy balance, adipocyte expansion, hypoxia, apoptosis and stress all lead to AT inflammation and dysfunction, and it has been demonstrated that this sick fat is a main risk factor for many metabolic disorders, such as type 2 diabetes mellitus, fatty liver, cardiovascular disease and cancer. AT dysfunction is tightly associated with aberrant secretion of bioactive peptides, the adipocytokines, and their blood concentrations often reflect the expression in the AT. Despite the existence of an association between AT dysfunction and systemic pro-inflammatory state, most of the circulating molecules detectable in obese and dysmetabolic individuals do not identify specifically the condition of sick fat. Based on this premise, thisreview provides a concise overview of "classic" and novel promising adipocytokines associated with AT inflammation and discusses possible critical approaches to their interpretation in clinical practice.

The color of fat and its central role in the development and progression of metabolic diseases.

Excess caloric intake does not always translate to an expansion of the subcutaneous adipose tissue (SAT) and increase in fat mass. It is now recognized that adipocyte type (white, WAT, or brown, BAT), size (large vs. small) and metabolism are important factors for the development of cardiometabolic diseases. When the subcutaneous adipose tissue is not able to expand in response to increased energy intake the excess substrate is stored as visceral adipose tissue or as ectopic fat in tissues as muscle, liver and pancreas. Moreover, adipocytes become dysfunctional (adiposopathy, or sick fat), adipokines secretion is increased, fat accumulates in ectopic sites like muscle and liver and alters insulin signaling, increasing the demand for insulin secretion. Thus, there are some subjects that despite having normal weight have the metabolic characteristics of the obese (NWMO), while some obese expand their SAT and remain metabolically healthy (MHO). In this paper we have reviewed the recent findings that relate the metabolism of adipose tissue and its composition to metabolic diseases. In particular, we have discussed the possible role of dysfunctional adipocytes and adipose tissue resistance to the antilipolytic effect of insulin on the development of impaired glucose metabolism. Finally we have reviewed the possible role of BAT vs. WAT in the alteration of lipid and glucose metabolism and the recent studies that have tried to stimulate browning in human adipose tissue.

Bariatric Endocrinology, Adiposopathy, and Disorders of Regional Fat Distribution

Bariatric Endocrinology, Adiposopathy, and Disorders of Regional Fat Distribution

Impact of Mediterranean diet on metabolic syndrome, cancer and longevity.

Obesity symbolizes a major public health problem. Overweight and obesity are associated to the occurrence of the metabolic syndrome and to adipose tissue dysfunction. The adipose tissue is metabolically active and an endocrine organ, whose dysregulation causes a low-grade inflammatory state and ectopic fat depositions. The Mediterranean Diet represents a possible therapy for metabolic syndrome, preventing adiposopathy or “sick fat” formation.The Mediterranean Diet exerts protective effects in elderly subjects with and without baseline of chronic diseases. Recent studies have demonstrated a relationship between cancer and obesity. In the US, diet represents amount 30-35% of death causes related to cancer. Currently, the cancer is the second cause of death after cardiovascular diseases worldwide. Furthermore, populations living in the Mediterranean area have a decreased incidence of cancer compared with populations living in Northern Europe or the US, likely due to healthier dietary habits. The bioactive food components have a potential preventive action on cancer. The aims of this review are to evaluate the impact of Mediterranean Diet on onset, progression and regression of metabolic syndrome, cancer and on longevity.

New obesity classification criteria as a tool for bariatric surgery indication.

Obesity plays relevant pathophysiological role in the development of health problems, arising as result of complex interaction of genetic, nutritional, and metabolic factors. Due to the role of adipose tissue in lipid and glucose metabolism, and low grade inflammation, it is necessary to classify obesity on the basis of body fat composition and distribution, rather than the simply increase of body weight, and the Body Mass Index. The new term of adiposopathy (''sick fat'') clearly defines the pathogenic role of adipose tissue. Four phenotypes of obese individuals have been described: (1) normal weight obese (NWO); (2) metabolically obese normal weight; (3) metabolically healthy obese; and (4) metabolically unhealthy obese or "at risk" obese. Moreover, sarcopenic obesity has been related to all the phenotypes. The category of normal weight lean, represented by metabolically healthy normal weight has been classified to distinguish from NWO. It is crucial to recommend a bariatric surgery taking into account adiposopathy and sick fat that occurs with the expansion of fat mass, changing the inflammatory and metabolic profile of the patient. Body fat percentage and genetic polymorphism have to be evaluated to personalize the best bariatric surgery intervention.

TENDINOPATHY AND OBESITY.

ABSTRACTIntroduction: Tendinopathies and tendon tears account for over 30% of all musculoskeletal consultations. Obesity, which is becoming one of the world´s most prevalent public health issues, may be associated with this condition.Objective: To review the literature about tendinopathies and obesity association.Methods: This is a descriptive exploratory study using the portal Medline. Literature in English language from 2006 to 2014 were reviewed.Results: The pathogenesis of tendinopathies includes inflammatory, regenerative and degenerative processes that happen simultaneously from early to late phases of the disease. Mechanical stress upon tendons seems to be one of the most important factors to initiate the inflammatory response, but it´s not the only one that can deflagrate it: there are other extrinsic, genetic and metabolic factors that may be involved. Therefore, tendinopathies in obese patients can be due to tendon overload because of the excess of weight, but also because of increased production of pro-inflammatory mediators related to fat tissue such as adipokines. This pro-inflammatory state that obese people can suffer is known as adiposopathy, or sick fat syndrome. Weight loss is associated with decrease in adipokines and improvement of musculoskeletal symptoms.Conclusion: The relation of obesity and tendinopathies is supported by evidences of recent studies, exemplified in this review of literature.

Not all fats are created equal: adipose vs. ectopic fat, implication in cardiometabolic diseases.

Adipose tissue is a recognized endocrine organ that acts not only as a fuel storage but also is able to secrete adipokines that can modulate inflammation. Most of the fat is composed of white adipocytes (WAT), although also brown/beige adipocytes (BAT/BeAT) have been found in humans. BAT is located close to the neck but also among WAT in the epicardial fat and perivascular fat. Adipocyte hypertrophy and infiltration of macrophages impair adipose tissue metabolism determining "adiposopathy" (i.e., sick fat) and increasing the risk to develop metabolic and cardiovascular diseases. The purpose of this review was to search and discuss the available literature on the impact of different types of fat and fat distribution on cardiometabolic risk. Visceral fat, but also ectopic fat, either in liver, muscle and heart, can increase the risk to develop insulin resistance, type 2 diabetes and cardiovascular diseases. Results recently published showed that BAT could have an impact on cardiometabolic risk, not only because it is implicated in energy metabolism but also because it can modulate glucose and lipid metabolism. Therapeutical interventions that can increase energy expenditure, successfully change fat distribution and reduce ectopic fat, also through BAT activation, were discussed.

Local adipocyte cancer cell paracrine loop: can "sick fat" be more detrimental?

This review article focuses on the emerging role of tumor resident adipocytes. It provides in vitro and in vivo evidence that they are essential for cancer development/progression. In addition to systemic effects, their tumor-promoting impact is dependent on local functions, notably via a complex adipocyte cancer cell paracrine loop (ACCPL). Indeed, this event leads to dramatic phenotypic and/or functional modifications of both cell types as well as of the extracellular matrix. Adipocytes undergo delipidation leading to adipocytes/cancer-associated adipocytes/cancer-associated fibroblasts de-differentiation processes. In turn, cancer cell aggressiveness is exacerbated through increased proliferation, migration, and invasion properties. This is accompanied by intense tissue remodeling, conducting to the occurrence of the tumor stroma. The molecular pathways involved in ACCPL remain largely unknown. Nevertheless, several clues are starting to emerge. Moreover, obesity is currently a sign of increased risk and poor prognosis in human carcinomas. How adiposopathy might impact tumors and specifically the ACCPL is still under investigation. However, available experimental, epidemiological, and clinical data allow to draw some directions. Interestingly, there are numerous similarities between the ACCPL-induced and obesity-related molecular alterations. It might, therefore, be hypothesized that obesity provides a "constitutively active" local permissive environment for cancer cells. Improving our knowledge about ACCPL in both lean and obese patients remains a challenging task. Indeed, deciphering the cellular and molecular mechanisms behind ACCPL might provide new targets for improving diagnosis/prognosis and the design of innovative therapeutic strategies, and even, in case of obesity, for preventing cancer.

Adiposopathy, "sick fat," Ockham's razor, and resolution of the obesity paradox.

Among lean populations, cardiovascular disease (CVD) is rare. Among those with increased adiposity, CVD is the commonest cause of worldwide death. The “obesity paradox” describes seemingly contrary relationships between body fat and health/ill-health. Multiple obesity paradoxes exist, and include the anatomic obesity paradox, physiologic obesity paradox, demographic obesity paradox, therapeutic obesity paradox, cardiovascular event/procedure obesity paradox, and obesity treatment paradox. Adiposopathy (“sick fat”) is defined as adipocyte/adipose tissue dysfunction caused by positive caloric balance and sedentary lifestyle in genetically and environmentally susceptible individuals. Adiposopathy contributes to the commonest metabolic disorders encountered in clinical practice (high glucose levels, high blood pressure, dyslipidemia, etc.), all major CVD risk factors. Ockham's razor is a principle of parsimony which postulates that among competing theories, the hypothesis with the fewest assumptions is the one best selected. Ockham’s razor supports adiposopathy as the primary cause of most cases of adiposity-related metabolic diseases, which in turn helps resolve the obesity paradox.

Body mass index and musculoskeletal pain: is there a connection?

BackgroundBack pain is one of the most common complaints that patients report to physicians and two-thirds of the population has an elevated body mass index (BMI), indicating they are either overweight or obese. It was once assumed that extra body weight would stress the low back and lead to pain, however, researchers have reported inconsistencies association between body weight and back pain. In contrast, more recent studies do indicate that an elevated BMI is associated with back pain and other musculoskeletal pain syndromes due to the presence of a chronic systemic inflammatory state, suggesting that the relationship between BMI and musculoskeletal pains be considered in more detail.ObjectiveTo describe how an elevated BMI can be associated with chronic systemic inflammation and pain expression. To outline measurable risk factors for chronic inflammation that can be used in clinical practice and discuss basic treatment considerations.DiscussionAdiposopathy, or “sick fat” syndrome, is a term that refers to an elevated BMI that is associated with a chronic systemic inflammatory state most commonly referred to as the metabolic syndrome. The best available evidence suggests that the presence of adiposopathy determines if an elevated BMI will contribute to musculoskeletal pain expression. It is not uncommon for physicians to fail to identify the presence of adiposopathy/metabolic syndrome.ConclusionPatients with an elevated BMI should be further examined to identify inflammatory factors associated with adiposopathy, such as the metabolic syndrome, which may be promoting back pain and other musculoskeletal pain syndromes.

Adiposopathy and Obesity Paradox

BACKGROUND: Obesity has reached global epidemic proportions in both adults and children and is associated with numerous comorbidities, including hypertension, type 2 diabetes mellitus (T2DM), dyslipidemia and major cardiovascular diseases (CVD).CONTENT: Adiposity may cause adipocyte and adipose tissue anatomic and functional abnormalities, termed adiposopathy (adipose-opathy) or "sick fat," that result in endocrine and immune derangements. Adiposopathy may directly contribute to CVD through pericardiac and perivascular effects on the myocardium and blood vessels. Adiposopathy may also indirectly contribute to CVD through promoting or worsening major CVD risk factors such as T2DM, high blood pressure, and dyslipidemia. Despite this adverse association, numerous studies have documented an obesity paradox in which overweight and obese people with established CVD, including hypertension, heart failure, coronary heart disease, and peripheral arterial disease, have a better prognosis compared with nonoverweight/nonobese patients. These paradoxical findings are made less paradoxical when the pathogenic potential of excessive body fat is assessed based on adipose tissue dysfunction rather than simply on increased fat mass alone.SUMMARY: Adiposopathy is defined as pathological adipose tissue function that may be promoted and exacerbated by fat accumulation (adiposity) and sedentary lifestyle in genetically susceptible patients. Adiposopathy is a root cause of some of the most common metabolic diseases observed in clinical practice, including T2DM, hypertension and dyslipidemia.KEYWORDS: adiposopathy, adiposity, obesity paradox, adipocyte dysfunction, adipose hypertrophy, adipose hyperplasia

Adiposopathy, Diabetes Mellitus, and Primary Prevention of Atherosclerotic Coronary Artery Disease: Treating “Sick Fat” Through Improving Fat Function with Antidiabetes Therapies

Both obesity and type 2 diabetes mellitus (DM) are worldwide epidemics, an association that is neither incidental nor coincidental. Adipose tissue is as an active endocrine and immune organ whose dysfunction (adiposopathy or "sick fat") is promoted by excessive caloric balance in genetically and environmentally susceptible patients. The resultant adiposopathic responses directly and indirectly contribute to pathologies leading to hyperglycemia, high blood pressure, and dyslipidemia--all major cardiovascular risk factors--as well as to cardiovascular disease (CVD) itself. Toward the goal of primary prevention of CVD among DM patients, clinical trial outcomes evidence support the use of antihypertensive agents, lipid-altering drugs, and antiplatelet agents. Some of the most proactive measures to reduce the onset of cardiovascular risk factors and potentially prevent the onset of DM are early and aggressive nutritional, physical activity, and lifestyle interventions. Such measures improve the functionality of adipose tissue, reduce adiposopathic responses, and thus improve glycemic, blood pressure, and lipid parameters--all of which would be expected to reduce CVD risk. Finally, if nutritional, physical activity, and lifestyle interventions are not successful, and if DM pharmacologic therapies are indicated, then the choice of anti-DM medications should take into consideration the effects of such agents on adipose tissue function and dysfunction, which in turn, affects major CVD risk factors and CVD.

Phentermine, topiramate and their combination for the treatment of adiposopathy (‘sick fat’) and metabolic disease

Positive caloric balance often causes pathologic adipocyte and adipose tissue anatomical and functional changes (termed adiposopathy or ‘sick fat’), which may lead to pathogenic adipocyte and adipose tissue responses and metabolic disease. Fat weight loss may improve adiposopathy, and thus improve metabolic disease in overweight patients. Unfortunately, the efficacy of non-surgical weight loss therapies is often limited due to redundant physiological systems that help ‘protect’ against starvation and/or negative caloric balance. One strategy to overcome these limitations is to combine weight loss drug therapies having complementary mechanisms of action, thereby affecting more than one physiologic process influencing body fat accumulation. Phentermine is a noradrenergic sympathomimetic amine approved for short-term treatment of obesity. Topiramate is a sulfamate-substituted monosaccharide derivative of the naturally occurring sugar monosaccharide D-fructose approved as a treatment for migraine headaches and seizure disorders. Although known to facilitate weight loss since its approval, topiramate monotherapy does not have a regulatory indication as an anti-obesity agent. Phentermine HCl/topiramate controlled-release (PHEN/TPM CR) is a combination agent containing immediate-release phentermine and controlled-release topiramate. Clinical trials involving thousands of patients demonstrate PHEN/TPM CR to be effective in improving the weight of patients, and also effective in improving adiposopathy-associated metabolic diseases. This review examines the pathophysiology of adiposopathy as a contributor to metabolic disease, the data supporting phentermine monotherapy, topiramate monotherapy and their combination as anti-obesity and anti-adiposopathy agents, and the preliminary evidence supporting PHEN/TPM CR as a generally well-tolerated and effective agent to improve metabolic disease.