Viewpoint 1

Abstract

What are subcutaneous fat cells really good for? Let's face it: In these days of ever slimmer top models and ‘fat-free-food’ maniacs, the answer to this question must seem all too obvious to the worldwide increasing number of communities that fight soaring obesity levels and related co-morbidities: ‘Fat is bad’ is the permanently perseverated echo of media and press releases. Yet, the very same question, perhaps omitting the attribute ‘subcutaneous’, would have been judged out of place in the times of Rubens and his peers. And, although we lack the privilege to admire similarly magnificent pictures, the same will have to be said, too, of earlier times, say 25 000 years bc, when statuettes like the ‘Venus of Willendorf’ were held in highest esteem (Fig. 1). Rubens: Venus and Adonis (left), Venus of Willendorf (right). This is not a review about the history of mind and aesthetics on the perception of fat. But these eclectic examples – and it is quite simple to find more in other cultures and epochs – may reveal a deeper insight into some very timely issues: Fat tissue, since prehistoric times, has signified good health and fertility. And – certainly not only by chance related to this: Just try to imagine beauty and eros without fat tissue as modelling ingredience. Are aesthetics and physiology intertwined? Are there biological underpinnings to these age-old socio-cultural preconceptions? In this viewpoint, we will argue that the subconscious notions of our ancestors about ‘the importance of being fat’ may be the result of evolutionarily hardwired wisdom. Ironically, it is only today, in the times of fat as the eminent public foe, that we begin to gain exciting insights into essential biological functions of fat cells. To better define the frame for the topic at hand, let us first consider the extremes. In principle, the proneness to become fat may be taken as a case in point of its importance. The thrifty-genotype hypothesis invokes an evolutionary survival advantage for organisms capable of building energy stores quickly and efficiently (1,2). However, it is not infrequent that too much of a good thing amounts to a bad one, and fat tissue is no exception to this rule. Excess of intraabdominal (i.e. visceral) fat mass is associated with significant metabolic and cardiovascular disease, a main threat to modern affluent societies (3,4). However, intentional weight loss in overweight individuals without comorbidities may even increase mortality (5,6). Furthermore, with respect to subcutaneous fat, the jury is still out on its pathophysiological significance. Suffice it to say that, in subcutaneous locations, increased fat mass may even be beneficial (3,7–12). Now, let's put the cart before the horse: What, if we did not have fat tissue at all? Coming from this other extreme, the answer appears clear-cut: We would not be better off. Lipatrophy and lipodystrophy result in severe metabolic and endocrine disease and premature death (13,14), not to mention the psychologically disturbing and socially negative disfigurement that comes along with it. Interestingly, implantation of fat tissue or administration of the fat cell-derived hormone leptin reverse or ameliorate these negative effects of fat loss (15,16). Thus, it appears, as if nature aims at striking the right balance that guarantees a well-titrated mass of fat tissue in the right location (and, one should add, at the right time): Fat mass is subject to physiological, age-dependent alterations in babies, children and adolescents. We know very little about the significance of ‘normal’ fluctuations later in life. Studies suggest that cardiovascular risk and mortality associated with an increased fat mass also vary with age (17,18). Taken together, the mechanisms critically determining fat distribution, depot-specific fat cell function, and age-dependent alterations of both, currently remain ill-understood. A complex interplay between environmental advantages (e.g. ‘cutting a better figure’ in an aqueous environment?) and endogenous factors (e.g. anatomical vicinity of metabolically active abdominal fat cells to the portal circulation of the liver?), can be hypothesized to have been at work in the progress of evolution. In this context, the so-called brown fat also needs to be mentioned. This specialized thermogenic tissue typically resides in subcutaneous interscapular and interaxillar locations. It enables newborn mammals to survive in the cold by generating heat at the cost of ATP production (19). Albeit regressing with age, the calorie-burning brown fat, scattered between subcutaneous and intraabdominal white fat cells, may be an interesting target for anti-obesity therapies – even more so, as transdifferentiation between energy-storing white and energy-combusting brown adipocytes does occur (20–22). Transdifferentiation also provides the cue for the concluding note of this section: On closer inspection, fat tissue turns out to be a rather enigmatic mixture of different cell types, most likely of predominantly mesenchymal origin. Next to inflammatory cells, subcutaneous fat appears to harbour an interesting and readily amenable reservoir of precursor cells with an astonishing capacity to differentiate into multiple tissues (23). Thus, the (trans)differentiation of preadipocytes into neurones, myogenic and osteogenic cell lineages has been reported. Simple autologous transplantation of subcutaneous fat tissue has successfully been employed to heal extensive skull defects in mice and humans (24,25). But now, let's turn to genuine metabolic and immuno-endocrine fat cell functions in the following two sections. Tissue-specific genetic engineering techniques have recently provided the opportunity to gain unexpected insights into the biological role of intracellular signalling pathways in fat cells. Suffice it to list two instructive examples: (1) Glucocorticoids play a key role in fat cell metabolism and differentiation (26). The enzyme 11β hydroxysteroid dehydrogenase type 1 (11β HSD-1) converts inactive cortisone into active glucocorticoid metabolites. When overexpressed in fat cells of transgenic mice, this enzyme induces the complete clinical picture of the metabolic syndrome with insulin resistance, obesity and dyslipidaemia (27). Conversely, the fat cell-specific genetic disruption of 11β HSD-1 or glucocorticoid inactivation conveys resistance against diet-induced abdominal obesity (28,29). (2) Fat is a classical target tissue of insulin action (30). As fat tissue only takes up about 10% of the entire insulin-induced whole body glucose uptake, fat cell insulin sensitivity was not considered very important for overall glucose homeostasis. Yet, a fat cell-specific disruption of the glucose transporter Glut4 impairs insulin action in muscle and liver and renders mice insulin-resistant (31). In contrast, a fat cell-specific gene knock-out of the insulin receptor results in protection against obesity and against an age-dependent impairment of glucose tolerance (32). Another surprising finding is the increase in longevity by approximately 20% (33). In fact, insulin/IGF-1 signalling pathways in fat tissue have been implicated in regulating the life span even in ancient, evolutionarily distant model organisms such as worms and fruit flies (34). In summary, the biological consequences of impaired signalling in fat cells remain complex. Yet, it has become evident that fat cell-specific alterations of intracellular signalling systems critically determine whole body energy homeostasis, lipid metabolism, insulin sensitivity and even longevity. Fat cells synthesize and secrete many lipid products and peptides, ‘adipokines’, which contribute to the control of a broad range of biological functions (35). This illustrates again the intimate interconnections between fat cell function and multisystem integrity. Optimizing energy management in response to changing conditions of food supply is pivotal to survival. Thus, it is reasonable to assume that an organism will adapt the activity of virtually every physiological system to maintain energy balance. Adipokines are emerging as important messengers in this communication network. In addition to the control of energy and glucose homeostasis, studies on an incessantly growing list of adipokines have unravelled direct influences on immune system function and inflammatory processes, atherosclerosis, haemostasis, blood pressure regulation and fertility, just to name a few (36,37). Examples for the clinical exploitation of fat cell factors are the successful treatment of monogenic obesity (38), lipatrophic diabetes (16) and hypothalamic amenorrhoea (39) by administering the prototypic fat cell-derived factor leptin. Next, the insulin-sensitizing hormone adiponectin and other adipokines are waiting in the wings for diverse therapeutic applications (21). As delineated above, recent discoveries have assigned fat cells an essential role in the control of vital physiological circuits, including energy homeostasis, reproduction and longevity. Based on these findings, a concept of fat tissue as a ‘critical link’ organ can be developed. Alright, you may say: In order to guarantee survival, it is of prime importance to optimize energy management. But, what are the further implications in a broader evolutionary context? Consider this: On the one hand, an individual organism needs to be protected against dangers, both from the ‘outside’ and the ‘inside’. An efficient defence against infections and internal ‘tumor surveillance’ are managed by a vigilant immune system. On the other hand, species-specific genes ‘want’ to be preserved. To this end, successful reproduction is a prerequisite matched by an intact endocrine system. What could go wrong, otherwise? An organism suffering from diseased immune and endocrine systems may be an easy prey because it is less fit to react by ‘fight or flight’; it may be prone to develop tumours because of a deranged tumor surveillance, and it may not be able to reproduce. Therefore, linking energy homeostasis to an intact endocrine and immune system represents an evolutionary advantage. We propose that fat cells meet exactly this challenge: They provide the direct coupling of energy management to immuno-endocrine regulatory functions (Fig. 2). They have evolved as ‘guardians of multisystem integrity’, thereby enhancing chances of survival. Concepts on fat cell function: adipose tissue as ‘critical link’ organ. Optimal energy management is of prime importance to secure survival. Furthermore, to preserve the species and to protect the individual organism, intact endocrine and immune functions are essential which confer reproductive success and fitness. Adipose tissue functions can be understood as the evolutionary direct coupling of these multi-system tasks. This concept guides future approaches to discover new biological functions and fat cell-based therapies. For example, if this notion is correct, it can be predicted that fat cell-derived factors influence other physiological systems – potentially enhancing fitness and survival. A provocative list includes regulation of muscle and bone mass, cardioprotection and cognitive function. Indeed, an adipose–muscle crosstalk has been partially elucidated with respect to insulin sensitivity (31,40), effects of leptin on bone mass (41) and myocardial infarct size (42) have been reported, and finally, leptin has been revealed to be critical for the developmental programming of neural projections (43,44). So, did anyone really ask the question what subcutaneous fat cells are good for? Well then, this may pass for an answer: Fat cells make us fit for fight or flight, they protect us against metabolic, endocrine, immune and cardiovascular disease, they help us reproduce, and they assist in building our central nervous system synapses (Fig. 3). Proven and proposed fat cell functions. We have already seen first examples of experimentally and clinically successful therapeutic uses of fat cell products such as leptin and adiponectin for seemingly unrelated metabolic and endocrine disorders (21). New indications along the paths outlined above may soon follow. And last but not least, fat depots harbour precursor cells with a clinically proven potential to transdifferentiate. Given all this, the glowing appraisal that fat tissue has received from our ancestors, may indeed subconsciously have been based on nuts-and-bolts biological facts. Therefore, to close with Shakespeare's famous quote on the purported virtues of ‘fat men’ from Julius Caesar (see Prelude 2), we would not be surprised to learn, one day, that fat cell products contribute to modulating our sleep, character traits and social behaviour. J.K. is a Feodor-Lynen fellow of the Alexander von Humboldt Foundation. This work was supported by the Deutsche Forschungsgemeinschaft (Kl 1131/2-5).