The Platform for Adipose Tissue Expansion during Positive Energy Balance
Year: 2012
Type: editorial
Abstract: Studies in adipose tissue gene expression and histology have focused largely on cross-sectional studies examining associations with measured metabolic parameters. These studies have contributed to our understanding of adipose tissue as a more active endocrine organ than previously envisioned. Yet, adipose tissue has the capacity to expand and contract more rapidly than other organs. Understanding the changes that occur with adipose tissue expansion/reduction may be crucial to preventing weight gain and aiding weight loss and maintenance. The study by Alligier et al. (1) in this issue of the JCEM examined early (at 14 d) and later (at 56 d) changes in whole adipose tissue gene expression and histology in individuals undergoing overfeeding. Not surprisingly, genes associated with lipid and fatty acid biosynthesis were increased early in overfeeding. The more compelling findings were those after 8 wk of overfeeding that demonstrated up-regulation of pathways involved in angiogenesis, extracellular matrix deposition, and the renin-angiotensin system (RAS) along with down-regulation of the cellular nutrient-sensing β-catenin-dependent Wnt pathway. Many of the previous microarray studies of differences in adipose tissue expression have examined these changes during weight loss over varying durations. As one might expect, in the majority of these studies, the gene expression changes that predominate are those related to macronutrient and, in particular, lipid and fatty acid metabolism (2–4). However, one study of longer duration (over 33 wk) found that the predominant down-regulated pathways involved function of the extracellular matrix and cell death (5). A few studies have examined changes in adipose tissue gene expression with overfeeding and weight gain. Consistent with the findings by Alligier et al. (1), Tam et al. (6) focused specifically on inflammatory gene expression and macrophage histology and found no changes in either with overfeeding over 28 d. In a shorter term overfeeding study of just 7 d, Shea et al. (7) noted multiple up-regulated pathways, including those involved in carbohydrate and lipid metabolism. The study by Alligier et al. (1) represents a significant advance because it investigated changes in gene expression coupled with histology over very short and longer periods of positive energy balance. The finding of the up-regulation in genes associated with angiogenesis is particularly relevant. The ability to increase its own vascular supply is essential to adipose tissue plasticity (8). Most convincing with regard to the study by Alligier et al. (1) is their confirmation of the adipose tissue expression with histological changes using a marker of endothelial cells (CD34 antibody) to demonstrate an increase in microvascular density after 8 wk of overfeeding. It is not hard to imagine that increased adipose tissue would require an increase in vasculature to support the expanded nutrient need. Adipose tissue vasculature appears to be a promising target for antiobesity therapy. Indeed, in leptin-deficient mice, administration of an angiogenesis inhibitor produced loss of body fat on par with administration of leptin (9). A peptide mimetic that specifically targets white adipose tissue vasculature has produced weight loss in mice (10) and more recently in an obese nonhuman primate model (11). Sustained reductions in fat mass can only occur if energy balance is altered. Therefore, modifications in adipose tissue vasculature that produce lasting weight loss must affect either energy expenditure or energy intake. Kim et al. (12) offered an intriguing mechanism to explain a potential role for adipose tissue vasculature in the energy balance equation. Using the same proapoptotic peptide used in the studies by Kolonin et al. (10) and Barnhart et al. (11), Kim et al. (12) induced weight loss in mice fed a high-fat diet (HFD). The alteration in energy balance occurred because these HFD mice reduced their energy intake compared with HFD mice vehicle-treated mice. No effect was seen on energy expenditure after accounting for changes in body weight. The decrease in food intake occurred despite reductions in circulating leptin and hypothalamic signals consistent with negative energy balance, specifically decreased gene expression of proopiomelanocortin. This reduction in food intake was also seen in the nonhuman primate models, indicating again that targeted disruption of adipose tissue vasculature produces decreases in food intake. The mechanism for this is unclear, but it indicates that angiogenic-derived signals in adipose tissue may modify hunger and satiety. By establishing the importance of angiogenesis with weight gain, Alligier et al. (1) have highlighted an important aspect of adipose tissue expansion in humans, and one that might be amenable to pharmacological therapy. Based on the present study, it is also clear that with long-term increases in fat mass, adipose tissue develops a well-designed supportive matrix. This consists not only of vascular structures but also increases in connective tissue, as highlighted by the increased gene expression seen in pathways involved in extracellular matrix remodeling. This includes structural proteins that may preserve adipose tissue composition and enzymes important for the turnover of these structural proteins. At least one collagen protein, COL6A3, has been associated with weight gain and resulting adipose tissue inflammation (13). With the increase in adipose tissue mass, there is also a down-regulation of pathways that can sense changes in energy availability and regulate cell metabolism. The Wnt-signaling pathway is important in this regard and has been implicated in tissue remodeling (14). This complicated pathway involves β-catenin-dependent and -independent pathways (referred to as the canonical and noncanonical Wnt pathway, respectively). In white adipose tissue, the β-catenin-dependent pathway inhibits adipogenesis via inhibition of two important transcription factors [PPARγ (peroxisome proliferator activated receptor) and C/EBPα (CCAAT-enhancer binding protein)] that aid in adipogenesis via differentiation of preadipocytes. The important aspect of the altered regulation of the Wnt pathway is its potential role at the crossroads between nutrient sensing and cell differentiation. At least in macrophages, evidence indicates that the Wnt pathway is sensitive to modifications in glucose even within the physiological range (15). However, in contrast to findings by Alligier et al. (1), glucose appears to stabilize β-catenin levels rather than reduce them. The Wnt pathway has diverse effects in different body tissues. How this pathway may respond to nutrient loads within adipose tissue, and thus alter cellular processes, is still far from clear. The final interesting aspect to this story is the finding of activation of the RAS. Well known for its role in blood pressure regulation, angiotensin II is also produced in white adipose tissue and appears to have a trophic effect (via angiotensin receptors 1 and 2) on adipose tissue development (16). Yet how the RAS system affects or is regulated by energy balance is far from clear. Initial reports indicated that mice lacking angiotensin II type 1a (Agtr1a) receptor have attenuated diet-induced weight and fat mass gain via increased energy expenditure (17). However, in a recent report, mice lacking this same receptor were reported to be hyperphagic when given ad libitum access to food (18). In this same study, pair feeding studies demonstrated that the Agtr1a knockout mice gained less weight compared with controls and had enhanced thermogenic response to cold, indicating that the RAS system may have a role in both sides of the energy balance equation. Of particular interest is that the Agtr1a knockout mice had decreased expression of CRH, an anorexigenic neuropeptide, in the hypothalamus, linking RAS pathways with hypothalamic signals that influence satiety. Thus, as in the case of angiogenesis, this furnishes at least preliminary evidence for how adipose tissue expansion and activated pathways may serve to alter satiety and make weight loss more difficult. As noted above, what is equally interesting about the work by Alligier et al. (1) is which aspects of adipose tissue gene expression and histology did not change. Despite longer term overfeeding and weight gain, they did not find increases in inflammatory gene expression or adipose tissue macrophages (ATM). In cross-sectional studies, ATM and ATM activation have been associated with adiposity and insulin action, respectively (19). Yet, a lack of coordinated increase in these macrophage markers or histology may indicate that macrophage accumulation in adipose tissue may be a secondary (and not necessarily causal) result of the other metabolic alterations that occur with increased adiposity. Alligier et al. (1) have made an important contribution to our overall knowledge of the expansion and remodeling of adipose tissue during prolonged positive energy balance. It is clear that over a more prolonged period the supportive structures (vascular and extracellular membrane) needed to maintain adipose tissue expansion begin to predominate. This is accompanied by down-regulation of apparent nutrient-sensing pathways that are the permissive to this tissue expansion. Unlike previous studies, Alligier et al. (1) also provide histological evidence of changes to support changes in expression. Additional work is still needed to validate these histological changes as clear evidence of an increase in adipose tissue capillaries and whether the density of adipose tissue capillaries can be determined. If so, this would be an important advance in understanding adipose tissue architecture and its alteration with changes in energy balance. Difficulty with weight loss may stem from the changes that occur in adipose tissue during more prolonged positive energy balance. The activation of pathways that promote and support this expansion may also alter important pathways that may also modify hypothalamic signaling, reduce satiety, and make calorie reduction more difficult. Future work should continue to concentrate on how adipogenic signals activated during alterations in energy balance may influence energy intake or expenditure to support this expansion. Studies such as the one presented here by Alligier et al. (1) provide an important framework to continue these investigations. This work was supported by the intramural research program of the The National Institute of Diabetes and Digestive and Kidney Diseases. Disclosure Summary: The author has nothing to declare. Angiotensin II type 1a adipose tissue macrophage high-fat diet renin-angiotensin system.
DOI: 10.1210/jc.2011-3320
Author: Jonathan Krakoff
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W2002509146