Journal of Molecular Medicine

, Volume 84, Issue 1, pp 1–3

A fat attack occurred in fat city

Authors

    • Franz Volhard Clinic, HELIOS Kliniken Berlin, Medical Faculty of the CharitéHumboldt University
Clinical Implications

DOI: 10.1007/s00109-005-0725-6

Cite this article as:
Luft, F.C. J Mol Med (2006) 84: 1. doi:10.1007/s00109-005-0725-6

Obesity has become a, if not the, major worldwide health risk problem. Cardiovascular disease is the commonest cause of death worldwide. The driving forces are arterial hypertension and diabetes. These two risk factors are mediated by a tremendous increase in obesity that affects all countries. In North America, the numbers of overweight {body mass index [BMI; body weight (kg)/height (m2)] >25} and obese (BMI >30) exceed those of normal BMI or below, who now constitute a minority! The Europeans, Asians, Africans, South Americans, and other populations are only shortly removed from this state of affairs. The implications are phenomenal and include a decreasing life expectancy for all-cause mortality related to increasing obesity across all populations [1]. The 4th International Symposium on Obesity and Hypertension was held in Berlin on 27–29 Oct 2005. This loosely connected group of investigators is particularly interested in the cardiovascular implications of obesity. Scientists from all over the world participated. The small size of this dedicated participant group assured a lively interchange. I have picked several investigators for my commentary.

Adipose tissue is associated with inflammation [2]. As a matter of fact, in insects, the major organ regulating innate immunity is the fat body that is equipped with bacterial and fungal Toll receptors. Similarly, fat in higher organisms is also involved in inflammation and immunity. Various inflammatory proteins are secreted directly from adipocytes and adipose-tissue-derived macrophages. Obesity is associated with increased local adipose inflammation largely due to tumor necrosis factor-α (TNF-α) up-regulation. Weight loss results in decreases in circulating C-reactive protein (CRP), interleukin-6 (IL-6), IL-18, plasminogen activator inhibitor-1 (PAI-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Angiotensinogen is secreted from adipose depots. Adipocyte-produced leptin may serve to activate monocytes. Serum amyloid A3 (SAA3) is an acute phase reactant that may also be produced by adipocytes.

However, adipocytes also produce protective factors. A decade ago, Philipp Scherer and his colleagues first described a novel serum protein similar to C1q that was produced exclusively by adipocytes [3]. The protein’s mRNA was induced 100-fold during adipocyte differentiation. The secretion of this abundant serum protein, first termed Acrp30, was enhanced by insulin. Their work suggested that the protein might be important to energy homeostasis, food intake, carbohydrate, and lipid catabolism. The protein they discovered is now known as adiponectin. Since their report, more than 1,500 papers have been published about adiponectin [4]. Adiponectin is a complex protein secreted specifically from adipocytes. Low adiponectin serum levels are causally linked to insulin resistance and are predictive for the development of diabetes and cardiovascular disease. A sexual dimorphism exists for plasma adiponectin levels, with significantly higher concentrations in women. Obesity is associated with decreased adiponectin levels.

Adiponectin is promising as a therapeutic agent in numerous animal experiments and human epidemiological studies. The protein is multifunctional, with protective roles against the development of insulin resistance, dyslipidemia, nonalcoholic fatty liver disease, atherosclerosis, cardiac hypertrophy, and ischemic injury. Furthermore, adiponectin may act in the brain to decrease body weight. However, the molecular mechanisms by which adiponectin achieves these effects are not yet understood. The production of recombinant adiponectin is challenging because of the complex tertiary and quaternary structure of the protein and the distinct activities of the different isoforms.

Adiponectin, like other adipokines (such as resistin), is secreted from the adipocyte as distinct complexes. Adiponectin forms trimers (the basic building block for the higher-order complexes), hexamers consisting of two trimers, and higher molecular weight (HMW) forms consisting of up to 12–18 subunits. Proper folding and assembly depend on posttranslational modifications that can be achieved only in mammalian production systems. Adiponectin contains a collagenous tail domain and a globular head domain. The subunits are linked through intermolecular cysteine bonds. A globular form of adiponectin produced in Escherichia coli possesses biological activity distinct from the mammalian-produced full-length protein. Interestingly, a mutant version of adiponectin that lacks a critical cysteine residue in the collagen domain is considerably more bioactive than wild-type adiponectin. Mice overexpressing this mutant form of adiponectin (Cys39Ser) in a genetically obese background (leptin-deficient ob/ob mice) display massive adipose tissue accumulation. Nevertheless, these morbidly obese animals are metabolically healthy and have nearly normal glucose and lipid levels. These observations suggest a processing step in the activation cascade for adiponectin that converts the HMW forms into the smaller short-lived trimers, possibly involving a serum reductase or protease.

Kadowaki and Yamauchi recently cloned adiponectin receptors in the skeletal muscle (AdipoR1) and liver (AdipoR2), which appear to comprise a novel cell-surface receptor family [5]. They showed that AdipoR1 and AdipoR2 serve as receptors for globular and full-length adiponectin and mediate increased adenosine monophosphate (AMP)-activated protein kinase, peroxisome proliferator-activated receptor-alpha ligand activities, and glucose uptake and fatty acid oxidation by adiponectin. Obesity decreases expression levels of AdipoR1/R2, thereby reducing adiponectin sensitivity, which finally leads to insulin resistance. A brief schematic of adiponectin signaling is given in Fig. 1.
Fig. 1

Adiponectin can activate the cyclic AMP kinase (AMPK) and PPAR-α in the liver and skeletal muscle. In skeletal muscle, both globular and full-length adiponectins activate AMPK, thereby stimulating phosphorylation of acetyl coenzyme-A carboxylase (ACC), fatty acid oxidation, and glucose uptake. Adiponectin activates PPAR-α, thereby also stimulating fatty acid oxidation and decreasing tissue triglyceride (TG) content in muscle. In liver, only full-length adiponectin activates AMPK, thereby reducing molecules involved in gluconeogenesis and increasing phosphorylation of ACC and fatty acid oxidation. PEPCK indicates phosphoenolpyruvate carboxykinase (adapted from [5])

Scherer’s work goes beyond adiponectin and touches on much of clinical medicine. For instance, his group found that adipocyte-derived collagen VI affects breast cancer progression in vivo. The implications are that a tumor–stromal environmental interaction exists dependent on fat. In this study, the authors proposed a model that involves adipocyte-derived collagen VI that is either produced at higher levels or has an increased half-life during tumor progression, presumably as a result of the local paracrine interactions between the tumor cells and the surrounding adipocytes. This fragment accumulates on tumor cells, where, through activation of the neural/glial cell 2 (NG2) receptor, the fragment triggers the activation of specific signaling pathways that involve β-catenin, leading to a further promitogenic response for the cancer cells. The data from the Scherer group implicate fat cells in breast tissue as direct participants in breast cancer progression [6].

Also fascinating is the observation by the Scherer group on the adipocyte as a target for Trypanosoma cruzi infections [7]. All cardiologists are aware that T. cruzi induces a cardiomyopathy that is associated with typical conduction delays in the electrocardiogram. However, in their study involving an adipocyte cell line, Combs et al. found that acute T. cruzi infection has a unique metabolic profile with a high degree of local adipose tissue inflammation, reduced adiponectin levels, hypoglycemia, hypoinsulinemia, and normal glucose disposal. Since epicardial fat is a known cardiac accompaniment that also serves as a cardiovascular risk factor, it would appear that fat is a reservoir for Chagas’ disease or perhaps other parasites.

Recently, the Scherer group described the generation and characterization of the first inducible “fatless” model system, the FAT-ATTAC mouse [8]. The acronym stands for “fat apoptosis through targeted activation of caspase 8”. This transgenic mouse developed no differently than did wild-type littermates. Apoptosis of adipocytes was induced at any developmental stage by administering a FK1012 analog that leads to the dimerization of a membrane-bound, adipocyte-specific caspase 8–FKBP fusion protein. Within 2 weeks of the dimerizer administration, FAT-ATTAC mice show near-knockout levels of circulating adipokines, and their fat, for all intents and purposes, disappeared. FAT-ATTAC mice were glucose-intolerant, had diminished basal and endotoxin-stimulated systemic inflammation, were poorly responsive to glucose-stimulated insulin secretion, and showed increased food intake independent of the effects of leptin. The group also showed that functional adipocytes recovered upon cessation of treatment, which allowed them to study adipogenesis in vivo. In future studies, the investigators will be able to study the adipocyte in its regulation of multiple physiological functions and pathological states.

No less interesting is the work of the group around Rudolf Zechner. The mobilization of fat as triglycerides stored in adipose tissue is mediated by hormone-sensitive lipase (HSL). However, gene-deleted HSL mice proved not to be fat. This state of affairs suggested to the investigators that other pathways exist that split triglycerides in adipose tissue. Zimmermann et al. [9] reported that a second enzyme called adipose triglyceride lipase (ATGL) catalyzes the initial step in triglyceride hydrolysis. ATGL contains a so-called “patatin domain” common to plant acyl hydrolases. ATGL was highly expressed in murine and human adipose tissue. ATGL exhibited high substrate specificity for triacylglycerol and was associated with fat droplets in fat cells. ATGL, together with HSL, coordinately breaks down stored fat in adipocytes. A recent comparison of obese and nonobese human subjects showed that obesity was associated with a decrease in catecholamine-induced lipolysis and HSL expression in mature fat cells and in differentiated preadipocytes [10]. Thus, HSL seems to be the major lipase for catecholamine- and natriuretic-peptide-stimulated lipolysis, whereas ATGL mediates the hydrolysis of triglycerides during basal lipolysis. Decreased catecholamine-induced lipolysis and low HSL expression may constitute a possibly primary defect in obesity.

Zechner’s group has subsequently investigated whether or not endothelial lipase, a recently discovered phospholipase, might represent an alternative mechanism for the uptake of phospholipid-derived fatty acids in murine lipoprotein-deficient adipose tissue [11]. This supposition indeed proved to be the case. When lipoprotein lipase (LPL) was expressed in adipose tissue and isolated murine adipocytes, endothelial lipase mRNA was not detectable. In contrast, mouse adipose tissue and isolated adipocytes that lacked LPL expressed large amounts of endothelial lipase mRNA. The cellular phospholipase activity in LPL-deficient fat was increased markedly compared to control fat and was inhibited to control levels by a specific endothelial lipase antibody. Fatty acids produced by endothelial lipase activity were absorbed by adipocytes and incorporated into the triglyceride moiety of adipose tissue. Their findings suggest that endothelial lipase activity in fat and other peripheral tissues might contribute to the tissue uptake of free fatty acids, which could have important implications for the metabolism of plasma lipoproteins.

This brief view into adipocyte biology reveals the hotbed of scientific investigation going on in this area. When we understand what happens inside the cell, we will be able to generate acceptable therapies. As Allyn Mark pointedly emphasized, obesity is not a behavioral problem; rather, obesity is a biological disturbance that will require pharmacological treatments. Cannabinoid receptor blockers, neurotransmitter reuptake inhibitors, and the novel agents likely to be developed from the excellent basic science presented here inspire confidence for optimism regarding this major health care problem.

Respectfully,

Friedrich C. Luft

Copyright information

© Springer-Verlag 2005