Exercise and Adipose Tissue Macrophages: New Frontiers in Obesity Research?

Obesity is a major public health problem in the twenty-first century. Mutations in genes that regulate substrate metabolism, subsequent dysfunction in their protein products, and other factors, such as increased adipose tissue inflammation, are some underlying etiologies of this disease. Increased inflammation in the adipose tissue microenvironment is partly mediated by the presence of cells from the innate and adaptive immune system. A subset of the innate immune population in adipose tissue include macrophages, termed adipose tissue macrophages (ATMs), which are central players in adipose tissue inflammation. Being extremely plastic, their responses to diverse molecular signals in the microenvironment dictate their identity and functional properties, where they become either pro-inflammatory (M1) or anti-inflammatory (M2). Endurance exercise training exerts global anti-inflammatory responses in multiple organs, including skeletal muscle, liver, and adipose tissue. The purpose of this review is to discuss the different mechanisms that drive ATM-mediated inflammation in obesity and present current evidence of how exercise training, specifically endurance exercise training, modulates the polarization of ATMs from an M1 to an M2 anti-inflammatory phenotype.

Effects of resveratrol in patients with type 2 diabetes mellitus on skeletal muscle SIRT1 expression and energy expenditure.

OBJECTIVES: The primary aims of the study were to examine the effect of resveratrol on skeletal muscle SIRT1 expression and energy expenditure in subjects with Type 2 diabetes mellitus (T2DM). BACKGROUND: Animal and in vivo studies indicate that resveratrol increases SIRT1 expression that stimulates PGC1α activity. Subsequent upregulation of AMPK and GLUT4 expression are associated with improved insulin sensitivity in peripheral tissues. METHODS: Ten subjects with T2DM were randomized in a double-blind fashion to receive 3g resveratrol or placebo daily for 12 weeks. Secondary outcomes include measures of AMPK, p-AMPK and GLUT4 expression levels, energy expenditure, physical activity levels, distribution of abdominal adipose tissue and skeletal muscle fiber type composition, body weight, HbA1c, plasma lipid subfraction, adiponectin levels, and insulin sensitivity. RESULTS: There was a significant increase in both SIRT1 expression (2.01 vs. 0.86 arbitrary units [AU], p = .016) and p-AMPK to AMPK expression ratio (2.04 vs. 0.79 AU, p = .032) in the resveratrol group compared with the placebo group. Although the percentage of absolute change (8.6 vs. -13.9%, p = .033) and percentage of predicted resting metabolic rate (RMR; 7.8 vs. -13.9%, p = .013) were increased following resveratrol, there was a significant reduction in average daily activity (-38 vs. 43.2%, p = .028) and step counts (-39.5 vs. 11.8%, p = .047) when compared with placebo. CONCLUSIONS: In patients with T2DM, treatment with resveratrol regulates energy expenditure through increased skeletal muscle SIRT1 and AMPK expression. These findings indicate that resveratrol may have beneficial exercise-mimetic effects in patients with T2DM.

Connecting the dots: molecular and epigenetic mechanisms in type 2 diabetes.

It is likely that the heritability of T2DM goes beyond simple genetic markers and involves epigenetic mechanisms. Neel's Thrifty Gene Hypothesis was expanded by Chakravarthy to include metabolic cycling and the dissonance between our stone-age genes with a space-age lifestyle. Further modifications of this hypothesis continued after recent developments in evolutionary and epigenetic research. At the molecular forefront, energy-sensing signaling pathways in T2DM, such as PGC1alpha, AMPK, O-GlcNAc and most recently SIRT1 have been shown to play key roles in oxidative stress, mitochondrial dysfunction, inflammation and glucolipotoxicity, which are the hallmarks of insulin resistance and T2DM, Furthermore, SIRT1, PGC1alpha and O-GlcNAc also regulate gene expression and may play a role in the epigenetic machinery, thus providing an explanation to how metabolism switches to either a 'thrift' or 'spend' mode depending on food availability. Separate evidence on adaptations to exercise further links T2DM with decreased physical activity. In this review, the major findings from the epigenetic, epidemiological, molecular and clinical forefronts are integrated and unified as a coherent hypothesis for the etiology and pathogenesis of T2DM. It is an opportune time to start connecting the dots to provide the much needed basis for a better understanding of T2DM and a more targeted approach to drug development and treatment strategies.

Triple jeopardy in the pituitary.

Aggressive pituitary tumors are rare the pathogenesis is not well established. The development of pituitary tumor after apoplexy has also been rarely reported. We describe the sequential development of Cushing's disease, apoplexy and aggressive pituitary tumor in the same patient. A 31-year old male presented with eutopic ACTH dependent Cushing's syndrome which failed initial pituitary surgery. He underwent subsequent bilateral adrenalectomy for control of hypercortisolism. An episode of pituitary apoplexy then occurred which was followed by the development of a null-cell pituitary tumor. This second tumor exhibited an aggressive behavior with invasion into the surrounding structures and systemic spread clinically. This case provides important evidence for the hypotheses of the pathogenesis of aggressive pituitary tumors which could have arisen from surviving adenoma cells following apoplexy or as a de novo development of pituitary carcinoma from cells which were not part of the original adenoma. This is the first report of a transformation of Cushing's disease to an aggressive and invasive null cell tumor after pituitary irradiation, apoplexy and surgery.

Management of hyponatremia.

Hyponatremia is an important electrolyte abnormality with the potential for significant morbidity and mortality. Common causes include medications and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Hyponatremia can be classified according to the volume status of the patient as hypovolemic, hypervolemic, or euvolemic. Hypervolemic hyponatremia may be caused by congestive heart failure, liver cirrhosis, and renal disease. Differentiating between euvolemia and hypovolemia can be clinically difficult, but a useful investigative aid is measurement of plasma osmolality. Hyponatremia with a high plasma osmolality is caused by hyperglycemia, while a normal plasma osmolality indicates pseudohyponatremia or the post-transurethral prostatic resection syndrome. The urinary sodium concentration helps in diagnosing patients with low plasma osmolality. High urinary sodium concentration in the presence of low plasma osmolality can be caused by renal disorders, endocrine deficiencies, reset osmostat syndrome, SIADH, and medications. Low urinary sodium concentration is caused by severe burns, gastrointestinal losses, and acute water overload. Management includes instituting immediate treatment in patients with acute severe hyponatremia because of the risk of cerebral edema and hyponatremic encephalopathy. In patients with chronic hyponatremia, fluid restriction is the mainstay of treatment, with demeclocycline therapy reserved for use in persistent cases. Rapid correction should be avoided to reduce the risk of central pontine myelinolysis. Loop diuretics are useful in managing edematous hyponatremic states and chronic SIADH. In all instances, identifying the cause of hyponatremia remains an integral part of the treatment plan.