Obesity, Metabolic Syndrome, and Osteoarthritis Require Integrative Understanding and Management.

For a long time, white adipose tissue (WAT) has been regarded as an inert tissue for energy storage. With the rapidly rising incidence of the components of the metabolic syndrome—obesity, diabetes mellitus type II, and hypertension—in the industrialized world, these diseases have attracted increasing attention in research and health politics. In parallel, WAT was recognized as an active endocrine and paracrine organ that plays an important role in the metabolic syndrome.1 Article p 1029 Various studies within the past decade indicated that WAT in obesity is characterized by a chronic low-grade inflammation with secretion of inflammatory cytokines and chemokines (see the Figure). Tumor necrosis factor-α was identified as the first molecular link between inflammation and obesity by Hotamisligil and coworkers: Expression of this cytokine was increased in WAT of obese mice2 and correlated with obesity-induced insulin resistance.3 Interleukin-6 (IL-6) is another cytokine critically involved in the pathogenesis of obesity and insulin resistance. The serum levels of IL-6 positively correlate with obesity in humans and predict the risk of development of insulin resistance and diabetes mellitus type 2.4 IL-6 is produced by a variety of metabolic tissues that include WAT, hepatocytes, β-cells, and skeletal muscle. Thus, circulating IL-6 could mediate a crosstalk between these organs that results in a downward spiral toward systemic insulin resistance and decreased insulin secretion.5 Furthermore, obesity was found to be associated with macrophage accumulation in murine and human WAT.6 Chemokines such as CCL2/monocyte chemoattractant protein-1 (MCP-1) and CCL3/macrophage inflammatory protein-1α were reported to be increased in WAT of obese mice and to contribute to insulin resistance and macrophage recruitment.7 Recently, a causal relationship between obesity, WAT inflammation, and insulin resistance was characterized for MCP-1 and its receptor CCR2: MCP-1 enhanced macrophage infiltration in WAT, insulin resistance, and hepatic steatosis …

Our friend and colleague Wayne Fenton asked to write this article for the Journal because of his desire to educate other psychiatrists about the treatment of schizophrenia, including what he recognized to be a growing problem with the metabolic syndrome. This lifelong passion, which he pursued from his psychiatry residency at Yale, through his directorship of Chestnut Lodge, to his position at NIMH as Director of the Division of Adult Translational Research and Associate Director for Clinical Affairs, ended tragically with his killing during an evaluation of a psychotic young man. Wayne had worked tirelessly to secure support for new drug discovery in the NIMH programs that he directed. The Journal will be initiating in 2007 a series of articles on the discovery of new mental illness treatments. We will dedicate this series to Wayne's memory and include with it a memorial of his life and contributions to the treatment of mental illness.

Calmodulin-dependent protein kinase kinase 2 as a novel therapeutic target against osteoarthritis

Background/Objectives: Osteoarthritis is a slowly evolving joint disorder defined by cartilage degradation, synovial inflammation, subchondral bone hardening, and the growth of osteophytes. Increasing evidence highlights the role of metabolic factors in osteoarthritis onset and progression. This study investigated the link between metabolic syndrome and the level of knee impairment in postmenopausal respondents suffering from knee osteoarthritis. Methods: A total of 200 participants aged 60–75 years with knee pain were enrolled in this observational cross-sectional study conducted between 2022 and 2023. The case group comprised 120 women with radiographically verified knee osteoarthritis (Kellgren–Lawrence grades II–IV), while 80 age-matched women without radiographic changes served as controls. Clinical and anthropometric measures, metabolic indicators, and radiographic findings were collected. Functional status was assessed using the Lower Extremity Functional Scale and the Lequesne Index. Results: The groups differed significantly with respect to the presence of metabolic syndrome, diastolic blood pressure, and fasting glucose level (p < 0.05). The metabolic syndrome showed modest but significant associations with radiographic knee damage (effect size 4.7%). After adjusting for smoking status and physical activity level, metabolic syndrome remained significantly associated with radiographic damage (effect sizes: 4.8 and 2.2%, respectively). Participants with osteoarthritis but without metabolic syndrome had better functional knee status compared to those with metabolic syndrome (p < 0.05). Conclusions: In postmenopausal women, metabolic syndrome is independently associated with radiographic knee damage and contributes to poorer functional outcomes in participants with knee osteoarthritis, underscoring its potential role as a modifiable risk factor.

Obesity and its associated complications, such as insulin resistance and non-alcoholic fatty liver disease, are reaching epidemic proportions in the developed world, primarily due to the increased availability of high caloric foods and the decrease in daily physical activity. It is well established that energy balance is critical for maintaining normal body weight and homeostasis. When caloric intake chronically exceeds energy expenditures, white adipose tissue stores excess energy in the form of triglycerides, leading to obesity and related complications such as type-2 diabetes, a condition also referred to as metabolic syndrome. In mice, the TGF- superfamily is implicated in the regulation of white and brown adipose tissues differentiation. The KCP protein is a secreted regulator of the TGF- superfamily pathways that can inhibit both TGF- and Activin signals while enhancing the Bone Morphogenetic protein (BMP) signaling. However, the effects of KCP on metabolism and obesity have not been studied in animal models. Thus, we examined the effects of KCP loss or gain of function in mice that were maintained on either a regular or a high fat diet. Loss of KCP sensitized mice to obesity and associated complications such as hepatic steatosis and glucose intolerance. In contrast, transgenic mice that expressed KCP in the kidney, liver and brown adipose tissues were resistant to developing high fat diet induced obesity and had significantly reduced white adipose tissue. KCP over-expression was able to shift the pattern of Smad signaling in vivo, to increase the levels of P-Smad1 and decrease P-Smad3, resulting in resistance to high fat diet induced hepatic steatosis and glucose intolerance. The data demonstrate that shifting the TGF- superfamily signaling with a secreted inhibitor or enhancer can alter the profile of adipose tissue to reduce obesity and can inhibit the initiation and progression of hepatic steatosis to significantly reduce the effects of high fat diet induced metabolic disease. In summary, the results of this suggest that altering TGF-β superfamily signaling pathway by a secreted protein can attenuate renal fibrosis and the negative effects of obesity induced metabolic syndrome. Provide a conceptual basis for the use of secreted protein or derivatives to attenuate profibrotic pathways that depend on continued TGF-β signaling and/or counteraction by BMPs may potentially provide a novel approach to translating the protective role of BMP-7 into clinical benefit.

The metabolic syndrome is a construct that has come into common usage over the last few decades. In 1956, Jean Vague1 first demonstrated that upper-body obesity determined predisposition to diabetes mellitus, atherosclerosis, gout, and renal calculi; however, it was the presentation of this concept by Gerald Reaven in his Banting Lecture in 19882 that initiated the current focus on this entity as a clinical and pathological construct. Dr Reaven suggested that 3 major conditions—non–insulin-dependent diabetes mellitus (type 2 diabetes mellitus), hypertension, and coronary artery disease—had an causal commonality (resistance to insulin-stimulated glucose uptake and hyperinsulinemia) and referred to this constellation of abnormalities as “syndrome X.” He did not include abdominal obesity in the original description, nor did he comment significantly on a potential clinical role for his observations. In fact, his concluding sentences stated, “What remains to be seen is the magnitude of the role that resistance to insulin-stimulated glucose uptake plays in the etiology of human disease. I can only hope that this presentation has outlined the possibilities for future efforts to answer this question.” Response by Kahn p 1818 Since that time, this construct has evolved conceptually and functionally into an entity that many refer to as a “syndrome.” More recently, there have been many questions about the legitimacy of this designation, summarized by Kahn et al3 in a September 2005 position statement for the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Their comments called into question many of the assumptions that underlay the designation of “syndrome,” and they posed the following key questions: How clear is the existing definition of the metabolic syndrome for diagnostic purposes? How useful is the syndrome definition in predicting cardiovascular disease (CVD) risk? Do the individual components of the syndrome convey “risk” …

Introduction: The inflammatory process underlies either osteoarthritis (OA) or metabolic syndrome. Systemic inflammation that occurs in the metabolic syndrome will result in the production of inflammatory cytokines and activation of macrophages and chondrocytes. This can affect the entire body including joints and the surrounding tissues, causing OA. Type 2 Diabetes Mellitus (DMT2) and hypertension are the first and second most common metabolic syndrome components found in OA patients. This study aimed to determine the relationship between metabolic syndrome and knee OA in DMT2 patients with hypertension. Methods: By using an analytic observational method and cross-sectional design, this study involved the medical records of patients with DMT2. The sample consisted of 50 medical records selected by using the purposive sampling technique and fulfilling the inclusion and exclusion criteria. Results: This study involved 25 medical records of patients with and without knee (genu) OA. The characteristics of the sample were as follows: 1 medical record of patient aged 36-45 years, 18 medical records of patients aged 46-55 years, 16 medical records of patients aged 56-65 years, 15 medical records of patients aged &gt; 65 years, 21 medical records of male patients, 29 medical records of female patients, 27 medical records with metabolic syndrome, and 23 medical records without metabolic syndrome. The association between metabolic syndrome and knee (genu) OA was analyzed by using the Chi-Square Test using the SPSS application, where the results showed a significance value of p &lt; 0.05 (p = 0.001). Conclusion: This study shows that there is a significant association between metabolic syndrome and knee (genu) OA.

Obesity and Atherogenic Dyslipidemia

Association of Metabolic Syndrome With Proximal and Synchronous Colorectal Neoplasm

Obesity and its consequences are arguably the chief public health problems facing the developed world. Obesity causes many fatal diseases, in particular cerebrovascular and cardiovascular disease. Acanthosis nigricans (AN) is a common cosmetic disability in pigmented ethnic groups. It may present with periorbital darkening or darkening of the neck or knuckles as well as acrochordons (skin tags) around eyelids, neck or axillae. The more classical AN of axillae and groins is less often a cosmetic disability, although it is an important physical sign. AN is very common in pigmented populations throughout the world, irrespective of domicile. It is rare in whites. AN is closely associated with all the features of the insulin-resistance syndrome (IRS), especially obesity. AN and IRS share a similar prevalence and epidemiology. IRS (also known as syndrome X or the deadly quartet) is characterized by insulin resistance (IR) and its associated conditions, including obesity, dyslipidaemia, hypertension and diabetes mellitus (DM) type II. The sequelae of IRS are cardiovascular and cerebrovascular disease. The origins of insulin resistance and its sequel, IRS, are debated. Insulin resistance can result from obesity. Also obesity usually presents before AN, hypertension or DM II. For these reasons it may be more helpful to recognize instead an obesity syndrome. The obesity syndrome is characterized by a genetically determined thrifty metabolism that protects subjects in famine conditions but which, in conditions of plenty, leads to weight gain with all its consequences, including hyperlipidaemia, hypertension, IR with DM II, and, in due course, cerebrovascular and cardiovascular disease. In pigmented races, AN is an important early manifestation of the obesity syndrome. AN helps identify persons at particular risk of developing the obesity syndrome, dyslipidaemia, hypertension and IR with DM II. Recognition of AN, therefore, offers important opportunities for health screening and preventative medicine.

An Evidence-Based Review of Exercise and Metabolic Syndrome

The Gut Microbiome and Joint Microbiome Show Alterations in Patients With Knee Osteoarthritis Versus Controls: A Systematic Review

Ageing-associated changes that affect articular tissues promote the development of osteoarthritis (OA). Although ageing and OA are closely linked, they are independent processes. Several potential mechanisms by which ageing contributes to OA have been elucidated. This Review focuses on the contributions of the following factors: age-related inflammation (also referred to as 'inflammaging'); cellular senescence (including the senescence-associated secretory phenotype (SASP)); mitochondrial dysfunction and oxidative stress; dysfunction in energy metabolism due to reduced activity of 5'-AMP-activated protein kinase (AMPK), which is associated with reduced autophagy; and alterations in cell signalling due to age-related changes in the extracellular matrix. These various processes contribute to the development of OA by promoting a proinflammatory, catabolic state accompanied by increased susceptibility to cell death that together lead to increased joint tissue destruction and defective repair of damaged matrix. The majority of studies to date have focused on articular cartilage, and it will be important to determine whether similar mechanisms occur in other joint tissues. Improved understanding of ageing-related mechanisms that promote OA could lead to the discovery of new targets for therapies that aim to slow or stop the progression of this chronic and disabling condition.

Case Presentation: E.C. is a 53-year-old postmenopausal female, referred for treatment of hypertension, with a family history of type 2 diabetes, hypertension, and coronary heart disease (CHD). Until learning that her blood pressure was “too high” during a routine physical examination, she felt well, and her postmenopausal symptoms had responded to hormone replacement therapy. She was not overweight (her body mass index [BMI] was 23.7 kg/m2), and the only abnormality on physical examination was a blood pressure of 145/95 RAR. Laboratory results revealed a normal blood count and urinalysis, with the following fasting plasma concentrations of relevant metabolic variables (in mg/dL): glucose 102, triglycerides (TG) 238, low-density lipoprotein cholesterol (LDL-C) 147, and high-density lipoprotein cholesterol (HDL-C) 52. E.C. is hypertensive and hypertriglyceridemic and at increased risk for CHD. Less obvious is that these metabolic abnormalities are highly likely to be the manifestations of a more fundamental defect—resistance to insulin-mediated glucose disposal and compensatory hyperinsulinemia, changes that greatly increase CHD risk.1,2⇓ The importance of insulin resistance as a CHD risk factor was first explicated in 1998, and the cluster of abnormalities likely to appear as manifestations of the defect in insulin action designated as syndrome X.1 Support for this notion has grown almost as fast as the names used to describe the phenomenon. The Adult Treatment Panel III (ATP III) has recently3 recognized the importance as CHD risk factors of a “constellation of lipid and nonlipid risk factors of metabolic origin,” designated this cluster of abnormalities as “the metabolic syndrome,” and indicated that “this syndrome is closely linked to insulin resistance.” Table 1 lists the criteria the ATP III stipulated be used to diagnose the metabolic syndrome, and a recent report4 has applied these criteria to the database of the Third National Health and Nutrition …

The metabolic syndrome, a combination of interrelated metabolic risk factors, is associated with insulin resistance and promotes the development of cardiovascular diseases and type 2 diabetes mellitus. There is a close link between inflammation and metabolic disease, but the responsible mechanisms remain elusive. The aim of this study was to identify differentially expressed genes in insulin-resistant skeletal muscle tissue of women with the metabolic syndrome compared with healthy control women. Women with the metabolic syndrome (n = 19) and healthy control women (n = 20) were extensively phenotyped, insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp, and a skeletal muscle biopsy was obtained. Gene expression levels were compared between the two groups by microarrays. The upregulated genes in skeletal muscle of the women with the metabolic syndrome were primarily enriched for inflammatory response-associated genes. The three most significantly upregulated of this group, interleukin 6 receptor (IL6R), histone deacetylase 9 (HDAC9) and CD97 molecule (CD97), were significantly correlated with insulin resistance. Taken together, these findings suggest an important role for a number of inflammatory-related genes in the development of skeletal muscle insulin resistance.