Obesity has become a global epidemic, with a significant portion of the population classified as overweight or obese. This condition is associated with numerous health complications, including type 2 diabetes, cardiovascular disease, and certain types of cancer. Weight loss strategies are often employed to combat obesity, but maintaining long-term weight reduction remains a substantial challenge. This article explores the role of adipocytes, or fat cells, during weight loss, examining their structural and functional changes, as well as the underlying biological mechanisms that contribute to weight regain.
Adipose Tissue: A Dynamic and Multifunctional Organ
Adipose tissue, once considered a passive storage depot for energy, is now recognized as a dynamic, multifunctional organ with diverse cell types. It houses the majority of stored energy as triglyceride, the primary target for regulation in long-term energy homeostasis. Adipocytes, the main cell type in adipose tissue, play a crucial role in storing and releasing energy.
The Discovery of Leptin and its Role in Hormone Imbalance
It wasn't until 1994 that adipose tissue's involvement in hormone imbalance and obesity became clear, thanks to Jeffery M. Friedman and colleagues' discovery of leptin. In healthy animals, leptin helps control hunger by communicating with the hypothalamus, signaling the brain to stop eating once enough food has been consumed. However, in obese patients, the brain develops decreased sensitivity to leptin's action, a phenomenon known as leptin resistance.
Weight Regain: A Major Obstacle in Obesity Treatment
Weight regain after weight loss is a substantial challenge in obesity therapeutics. Dieting leads to significant adaptations in the homeostatic system that controls body weight, promoting overeating and relapse to obesity. Weight loss strategies are only transiently effective for most people, as the vast majority of individuals who attempt to lose weight are not able to achieve and maintain a 10% reduction over a year. Over a third of lost weight tends to return within the first year, and the majority is gained back within 3 to 5 years.
The Biological Drive to Regain Weight
There is substantial evidence for a biological drive to regain weight after weight loss. The biological control of body weight involves a complex feedback loop between the brain and periphery. The brain receives signals from the periphery regarding long-term energy stores (i.e., adipose tissue triglyceride) and short-term nutrient availability (i.e., immediate availability of circulating nutrients) and, based upon these integrated signals, adjusts energy balance to meet both the long-term and the short-term objectives of energy homeostasis.
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The Energy Gap: A Key Factor in Weight Regain
Peripheral signals create an ‘anabolic’ neural profile in the hypothalamus and hindbrain, increasing appetite and sending neuroendocrine efferent signals to enhance metabolic efficiency in peripheral tissues. This adaptive response involves coordinated changes in the brain, gut, muscle, liver, adipose tissue, and neuroendocrine system, which culminate in a concerted effect on energy balance. Metabolic requirements decline as a function of (i) lost mass, (ii) reduced consumption of food, and (iii) increased metabolic efficiency of peripheral tissues. Signals from the periphery convey to the brain that energy stores are depleted and nutrient availability is low, and these signals integrate in key circuits of the hypothalamus and hindbrain, which serve as the primary control centers for energy balance regulation. The response to these integrated signals is that appetite increases and the expenditure of energy declines.
This quantitative difference between the caloric value reflecting appetite and expenditure requirements is referred to as the energy gap. To maintain the reduced weight, food intake must be cognitively (in humans) or forcefully (in animals) restricted to the level that expended energy is suppressed. During weight maintenance after weight loss, this energy gap reflects the magnitude of the daily burden that thwarts cognitive efforts to maintain the reduced weight. When efforts to restrict intake fail, overfeeding occurs, and the excess nutrients are rapidly cleared and stored, and the relapse to obesity begins. This pressure to continue to overfeed generally persists until the lost weight returns.
Homeostatic Adaptations to Weight Loss
Neuroendocrine signals from the periphery convey a message of energy depletion (low leptin and insulin) and low nutrient availability (favoring signals of hunger over satiety/satiation) to the brain. Trafficking of absorbed nutrients (glucose, Glu; free fatty acids, FFA; triglycerides, TGs) to and from circulation is shown for both postprandial and post-absorptive metabolic states. Enhanced nutrient clearance reduces postprandial excursions in Glu and TGs and potentiates the postprandial suppression of FFAs, which may also convey a signal of nutrient deprivation to the brain. The signals of energy depletion and nutrient deprivation create an ‘anabolic’ neural profile in the hypothalamus and hindbrain, increasing appetite and sending efferent signals to enhance metabolic efficiency in peripheral tissues. The reduced metabolic mass, enhanced metabolic efficiency, and lower thermic effect of food contribute to the suppression of energy expenditure. A large energy gap is created between appetite and expenditure, and food intake must be cognitively (in humans) or forcefully (in animals) restricted to maintain the reduced weight.
The Energy Gap in Diet-Induced Obesity Models
A fundamental understanding of this energy gap, dictated solely by biological pressures, has emerged from preclinical studies of weight regain in diet-induced obesity (DIO) models. The energy gap at the maintenance-relapse transition is influenced in predictable ways by diet composition, by the length of time in weight maintenance after weight loss, and by physical activity levels. Weight regain driven solely by this biological pressure reflects a first-order growth curve such that the energy gap diminishes as the relapse to obesity progresses. As such, the magnitude of the energy gap is greatest at the nadir weight after weight loss. Furthermore, this energy gap does not dissipate with time in weight maintenance. Rather, studies indicate that the magnitude of the energy gap gradually increases the longer an animal maintains their reduced weight with an energy-restricted diet.
Adipocyte Cellularity and Weight Loss
White adipose tissue is a critical node in the homeostatic system that controls body weight and it plays a particularly important role in the biological drive to regain lost weight. The adipocyte serves its primary purpose of long-term storage of energy and as weight is gained, lost and regained, adipocytes and their support cells must undergo a substantial amount of remodeling to accommodate the gain or loss of stored energy. Weight loss is accompanied by a dramatic reduction in the size of adipocytes, which is reversed when weight is regained.
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Adipocyte Size: A Key Variable in Weight Loss and Regain
Studies in both humans and rodents suggest that adipocyte size is the most changeable aspect of cellularity characteristics in studies of weight loss and regain. During weight loss, energy stores are mobilized from adipocytes, and adipocytes become smaller. During weight gain and weight regain, energy is accumulated, and adipocytes become larger. The broad range for adipocyte size provides enormous flexibility for the amount of energy that can be stored at any one time. However, as adipocytes change size with the mobilization or accumulation of energy, the extracellular matrix must be remodeled to accommodate the change or a considerable mechanical strain will be imposed upon the adipocytes.
Mariman has hypothesized that weight loss causes cellular stress in adipocytes, resulting in an altered metabolic profile that would relieve the stress via increased storage of lipid.
Adipocyte Number: Stability and Turnover
Weight loss does not lead to any discernible change in the number of adipocytes in adipose tissue. The number of adipocytes in a normal, healthy individual remains relatively constant throughout adulthood, but there are conditions in which the number of adipocytes in particular adipose depots may increase. Studies in a rodent paradigm of weight loss and regain suggest that the metabolic conditions during the relapse to obesity may provide the conditions that promote hyperplasia. Early in the relapse process, the emergence of a population of very small adipocytes, which was accompanied by an increase in the total number of adipocytes in the depot, has been observed. This increase in cell number persisted throughout the relapse process as all of the adipocytes became larger. It has been speculated that this increased cell number partially explains animals in this model surpassing their pre-weight loss weight following relapse.
While substantiating the temporal changes in cell size frequency distribution and total cell number in humans presents a logistical challenge, a hypercellularity phenomenon with similar characteristics has been reported in post-obese humans. Even so, this relapse-induced hyperplasia of adipose tissue, if it does occur, is likely limited to individuals who have a genetic predisposition for obesity. There is very little evidence that the number of adipocytes is ever reduced under normal metabolic conditions associated with changes in weight.
Because the number of adipocytes was observed to be relatively stable in normal, healthy adults, it was long thought that the adipocytes produced by puberty represented the population of cells that persisted throughout life. Tracer studies have discounted this notion by revealing that new adipocytes are being produced and mature adipocytes are being cleared with some regularity. A wide demographic study of Swedish adults observed that the turnover rate for adipocytes is approximately 8-10% per year. The generation of new adipocytes involves two distinct steps: (i) the proliferation of preadipocytes and (ii) the differentiation of preadipocytes into functioning adipocytes, capable of storing and releasing energy. The clearance of mature adipocytes is less understood, but is known to involve the recruitment of macrophages. The crown-like structures that are observed in adipose tissues represent adipocytes targeted for clearance, surrounded by the recruited macrophages.
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The development of obesity is accompanied by a higher absolute amount of turnover, which is reflected in their greater fat mass and higher number of total adipocytes in their depots. The generation of new cells and the clearance of mature cells remains, in general, balanced at a higher level in the obese. When adjusted for the difference in fat mass, the actual rate of cell turnover per unit fat mass is similar. At present, we do not know how adipocyte turnover is affected with weight loss or during the process of weight regain. However, if hyperplasia does occur, there must be some transient imbalance between new cell generation and mature cell clearance to account for the difference in cell number.
Gene Expression and Metabolic Function in Adipocytes
Adipose tissues experience a global down-regulation of gene expression in obese subjects in response to energy-restricted weight loss, which includes all of the key metabolic pathways. However, this effect is partly reversed at the transition to weight maintenance. With weight maintenance and during weight regain, an expression profile that would enhance energy conservation and the repletion of energy stores emerges. Markers of oxidative stress and inflammatory cytokines, which are also known to suppress appetite and increase expenditure, decline. The impaired induction of lipogenesis by insulin, glucose, and feeding associated with obesity resolves after energy-restricted weight loss. Finally, the enhanced metabolic response to ingested energy enhances nutrient clearance during weight maintenance and during sustained periods of overfeeding.
Insulin sensitivity is inversely related to the size of the adipocyte. Compared with large adipocytes, small adipocytes exhibit higher rates of insulin-stimulated glucose uptake, higher levels of glucose oxidation, and a lower sensitivity to the antilipolytic action of insulin. In addition, smaller adipocytes exhibit a lower basal and catecholamine-induced lipolysis, have a lower rate of turnover of stored lipid, and express genes favoring energy storage. The higher lipolytic capacity and triglyceride turnover in larger adipocytes is associated with higher levels of Adipocyte triglyceride lipase (ATGL), Hormone sensitive lipase (HSL), and Lipoprotein lipase (LPL). De novo lipogenesis is also down-regulated as adipocytes increase in size.
Varlamov et al. suggested that this relationship between cell size and metabolic function serves to protect against lipid overload and continual expansion, which could eventually have deleterious consequences for the health of the cell. It was suggested that when the adipocyte size approaches a critical threshold in an individual (∼100 μm).
Adipose Tissue Inflammation and Weight Loss
Obesity is associated with subclinical white adipose tissue inflammation, as defined by the presence of crown-like structures (CLSs) consisting of dead or dying adipocytes encircled by macrophages. Obese subjects lost approximately 10% body weight over a mean of 46 days. CLS density increased in subcutaneous adipose tissue without an associated increase in proinflammatory gene expression. Weight loss was accompanied by decreased fasting blood levels of high-sensitivity C-reactive protein, glucose, lactate, and kynurenine, and increased circulating levels of free fatty acids, glycerol, β-hydroxybutyrate, and 25-hydroxyvitamin D. Rapid weight loss stimulated lipolysis and an increase in CLS density in subcutaneous adipose tissue in association with changes in levels of circulating metabolites, and improved systemic biomarkers of inflammation and insulin resistance.
Inflamed adipose tissue is believed to contribute to obesity-associated complications. This is characterized by immune-cell infiltration, increased levels of proinflammatory cytokines, as well as adipocyte insulin resistance, mitochondrial dysfunction, and endoplasmic reticulum stress. Crown-like structures (CLSs) are found in the white adipose tissue of both obese mice and humans. In cross-sectional studies, the presence of CLSs is associated with insulin resistance, cardiovascular disease (CVD), and worse prognosis for patients with cancer. These inflammatory foci represent dead or dying adipocytes enveloped by macrophages. The macrophages rely on lysosomal exophagy to phagocytose the dead adipocytes and become foam cells.
In obese rodents, prolonged caloric restriction is associated with a reduction in CLS and reduced expression of proinflammatory genes. By contrast, rapid weight-loss results in increased macrophage infiltration in visceral and subcutaneous adipose tissue. In humans, bariatric surgery-induced weight loss leads to a reduction in CLSs, improved systemic inflammation, and decreased insulin resistance and, possibly, cancer risk. Very-low-calorie diet (VLCD)-mediated rapid weight loss leads to a substantial reduction in fat mass in association with improved insulin sensitivity, reduced circulating triglyceride and cholesterol levels, as well as changes in subcutaneous fat gene expression.
Metabolic Memory: The Persistence of Obesogenic Changes
Strategies relying on behavioral and dietary changes frequently only result in short-term WL and are susceptible to the ‘yo-yo’ effect, in which individuals regain weight over time. This recurrent pattern may be partially attributable to an (obesogenic) metabolic memory that persists even after notable WL or metabolic improvements. Indeed, lasting phenotypic changes from previous metabolic states, that is, metabolic memory, have been reported in mouse adipose tissue (AT) or the stromal vascular fraction (SVF), whereas in the liver these were reversible. Persistent alterations after WL in the immune compartment and transcriptional and functional memory of obesity in endothelial cells of many organs have also been reported.
Epigenetic mechanisms and modifications are essential for development, differentiation, and identity maintenance of adipocytes in vitro and in vivo but are also expected to be crucial contributors to the cellular memory of obesity. For example, lasting chromatin accessibility changes have been associated with pathological memory of obesity in mouse myeloid cells and, also, cold exposure studies have indicated the existence of (epigenetic) cellular memory. Hitherto, most human studies have focused on DNA methylation analysis in bulk tissues or whole blood to assess putative cellular memory. These reports might be confounded by variations in cell type composition, which are poorly characterized in the AT during WL, and therefore serve foremost as indicators of cellular epigenetic memory.
It remains unresolved whether individual cells retain a metabolic memory and whether it is conferred through epigenetic mechanisms. Studies using single-nucleus RNA sequencing (snRNA-seq) of AT from individuals living with obesity before and after significant WL, as well as lean, obese, and formerly obese mice, confirm the presence of retained transcriptional changes. Further characterization of the epigenome of mouse adipocytes reveals the long-term persistence of an epigenetic obesogenic memory.
Transcriptional Changes in Human Adipose Tissue
To explore whether signatures of previous obesogenic states persist in humans after appreciable WL, subcutaneous AT (scAT) and omental AT (omAT) biopsies were obtained from individuals with healthy weight who have never had obesity and people living with obesity (but without diabetes) before and 2 years after BaS from multiple independent studies. Only patients exhibiting a minimum of 25% body mass index (BMI) reduction were included in the study. snRNA-seq on pooled omAT per group annotated 18 cell clusters in the omAT samples, including adipocytes, adipocyte progenitor cells (APCs), mesothelial cells, immune cells, and endothelial cells. Although consistent cellular composition differences between T0 and T1 in omAT were not observed, inter-individual cellular composition variations after single nucleotide polymorphism (SNP)-based demultiplexing were observed, possibly also affected by sampling during surgery. Notably, cell type-specific gene expression analysis revealed that many differentially expressed genes (DEGs) at T0 (obese versus healthy weight) were also deregulated at T1 in both studies.
Similar analysis with scAT biopsies annotated 13 cell clusters for scAT, including APCs, adipocytes, endothelial cells, and immune cells. Similar to omAT, it was found in both studies that many cell types retained transcriptional differences from T0 to T1. A further detailed analysis of cell type-specific gene expression changes in omAT and scAT showed that transcriptional deregulation during obesity was most pronounced in adipocytes, APCs, and endothelial cells. In line with this observation, the absolute number of retained DEGs from T0 to T1 was highest in these cell types as well.
Given that adipocytes showed strong retainment of transcriptional differences in each individual sample, the snRNA-seq data of all adipocytes from the omAT and scAT studies were integrated, respectively, and differential gene expression analysis was performed. Pooled omAT adipocytes displayed a strong retention of downregulated DEGs, including relevant metabolic genes such as IGF1, LPIN1, IDH1, or PDE3A. Similarly, the retention of downregulated DEGs in scAT adipocytes was pronounced and included relevant metabolic genes such as IGF1, DUSP1, GPX3, and GLUL.
Gene set enrichment analysis (GSEA) of retained DEGs in adipocytes of each study showed persistent downregulation of pathways linked to adipocyte metabolism and function and persistent upregulation of pathways linked to fibrosis (related to TGFβ signaling) and apoptosis. These results indicate that obesity induces cellular and transcriptional (obesogenic) changes in the AT, which are not resolved following significant WL.
Transcriptional Obesogenic Memory in Mice
Considering the observations of persistent transcriptional changes in human AT, mouse epiAT cellular changes throughout obesity and WL were examined using snRNA-seq. Fifteen key cell populations were annotated using common marker genes, including APCs, immune cells, adipocytes, mesothelial cells, endothelial cells, and epithelial cells. Consistent with previous findings, macrophage cell number in epiAT was higher in obese conditions (H and HH) and was not fully normalized after WL, especially in HHC mice. Resident macrophages in control mice (C, CC, and CCC) primarily consisted of perivascular macrophages and non-perivascular macrophages. Notably, during obesity, mainly lipid-associated macrophage (LAM) and non-perivascular macrophage cell numbers increased in the epiAT, altering the macrophage population composition persistently.
Based on the number of DEGs in each cell type, stronger transcriptional deregulation in obesity and after WL in adipocytes, APCs, endothelial cells, epithelial cells, and macrophages than in other cell types was found, corroborating the existence of persistent, cell-specific transcriptional changes in mouse epiAT. Indeed, across cell types, many DEGs from the obesity time point remained deregulated after WL. GSEA of retained DEGs in adipocytes, APCs, endothelial cells, LAMs, non-perivascular macrophages, perivascular macrophages, and mesothelial cells showed persistent upregulation in HC and HHC mice of genes related to lysosome activity, apoptosis, and other inflammatory pathways, indicating endoplasmic reticulum and cellular stress. Persistently downregulated retained DEGs in HC and HHC mice were mainly related to metabolic activity.
The Discovery of a New Source of Brown Fat Cells
A new source of energy-expending brown fat cells has been uncovered by Harvard Medical School researchers at Joslin Diabetes Center, which they said points towards potential new therapeutic options for obesity. Specifically, the authors point to smooth muscle cells expressing the Trpv1 (temperature-sensitive ion channel transient receptor potential cation subfamily V member 1) receptor and identify them as a novel source of energy-burning brown fat cells (adipocytes). Brown fat, or brown adipose tissue, is a distinct type of fat that is activated in response to cold temperatures. Its primary role is to produce heat to help maintain body temperature, and it achieves that by burning calories.
The source of these energy-burning fat cells was previously considered to be exclusively related to a population of cells that express the receptor Pdgfrα (platelet-derived growth factor receptor alpha). However, wider evidence suggests other sources may exist. The team initially investigated the general cellular makeup of brown adipose tissue from mice housed at different temperatures and lengths of time. Notably, they employed modern single-cell RNA sequencing approaches to try to identify all types of cells present.
As well as identifying the previously known Pdgfrα-source of energy-burning brown fat cells, their analysis of the single-cell RNA sequencing data suggested another distinct population of cells doing the same job-cells derived from smooth muscle expressing Trpv1. Further investigations with mouse models confirmed that the Trpv1-positive smooth muscle cells gave rise to the brown energy-burning version of fat cells especially when exposed to cold temperatures.
Further studies are now planned to address the role of the Trpv1 channel and its ligands and whether it is possible to target these cells to increase numbers of thermogenic adipocytes as a therapeutic approach towards obesity.
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