TRIMMED off meat or Iiposuctioned off our bodies, adipose tissue is widely abhored. 快猫短视频s study it mainly to plot its destruction. Even obesity researchers have seldom regarded adipose tissue as worthy of research in its own right. But all that may be about to change.
You see, fat is not, as biologists used to think, some sort of 鈥淐inderella tissue鈥�, just tucked into the holes and corners shunned by tissue with a higher status. Quite the reverse: mammalian fat cells, or adipocytes, are meticulously organised, grouped into about a dozen special depots around the body. What鈥檚 more, many of these fat depots do far more than simply store energy. They seem to have specialised functions linked to their location, be it on the heart, in muscle, or in surrounding lymph nodes.
One of the chief architects of this new view is Caroline Pond, a zoologist who works on a shoestring in one of Britain鈥檚 more beleaguered academic institutions, the Open University. 鈥淪ingle-handedly she has challenged the centuries-old view that 鈥榝at is just fat鈥�,鈥� says Andrew Prentice, head of obesity research at the Medical Research Council鈥檚 Dunn Nutrition Unit in Cambridge. Her work has established that adipose tissue has an evolutionary history and many roles.
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The latest findings from Pond鈥檚 laboratory, and the most revolutionary to date, suggest that some adipocytes act as both nurse and nanny to cells of the immune system. The fat cells seem to supply white blood cells with vital nutrients and may even help to control local immune responses. These are heretical ideas, and she expects many of her scientific colleagues to be sceptical. But Pond is accustomed to 鈥減loughing a lone furrow, a very imaginative and original one鈥�, remarks Paul Racey, professor of natural history at the University of Aberdeen.
The key to Pond鈥檚 research is that she studies fat tissues in a multitude of different mammals, some wild, some laboratory-reared. By contrast, most research into obesity that is funded by pharmaceuticals companies, and devoted to making women skinnier, is based on research on fat cells in rats. More than that, it is often confined to the large wodges of fat found on top of a rat鈥檚 kidneys or testicles. Researchers have focused unwittingly on the biggest but least metabolically active depots, says Pond, while 鈥渕uch of the interesting biochemistry is going on in the dustbin鈥�.
For Pond, all this reflects the history of fat research 鈥� or rather the lack of it. Victorian comparative anatomists wrongly believed fat tissue had no organisation or specific biological functions that could be explained as evolutionary adaptations. For years, laments Pond, the most abundant tissue in the body was barely mentioned in textbooks and thrown away during dissections.
Her fight against this 鈥渢issue chauvinism鈥�, as she wryly calls it, began in 1982 when she started 鈥減icking up 鈥榡unk鈥� animals as 19th-century anatomists would have done鈥�. She dissected wild animals, young and old, obese, lean or emaciated, looking for clues to the natural organisation and diverse roles of adipose tissue in mammals. Respectful of animal life, she took her time. She got on her bike and cycled around her home town at night, seeking wild animals killed by cars.
鈥淚 picked up all sorts of mammals killed accidentally along the roadside: badgers, hedgehogs, foxes and muntjac deer 鈥� descendants of escapees from the Duke of Bedford鈥檚 estate at Woburn.鈥� Soon, local gamekeepers, zookeepers and even police officers were helping with her enquiries. Night after night she worked in her laboratory, dissecting the casualties to chart the distribution and cellular structure of their fat.
As she dissected more and more animals, she began to see a consistency of organisation within a species, as well as between different species. Fat in mammals, it turns out, is organised into about a dozen precise locations, or depots. Some of these depots are large, accounting for more than a quarter of the animal鈥檚 total fat, and some are exceedingly small, contributing only a per cent or two to the total. And as the animal grows fatter, some depots expand disproportionately, while others hardly change. So the common notion that fat is only distributed in a continuous layer as 鈥渟ubcutaneous鈥� fat, or is merely stashed away in any old place couldn鈥檛 be further from the truth. On the contrary, it is positioned around the body in discrete patches within muscles, on the heart and around lymph nodes.
But why? Until now, says Pond, there has never been any satisfactory explanation as to why mammals would go for this somewhat irrational organisation of tissue. 鈥淭here is bags of room in the abdomen; if you can get twins into the abdomen, you can get a bit more adipose tissue in there.鈥�
It is easy to ignore such anomalies, and that is just what doctors and scientists have done for decades on end. The fatty tissue frequently observed on human hearts, for instance, was simply written off as some ill-defined 鈥減athology鈥� of modern life. Yet Pond found fat on the hearts of lean, as well as naturally obese, wild badgers, foxes, bears and reindeer, too. 鈥淭he adipose tissue in this site might account for a tiny fraction 鈥� perhaps a half of a per cent of the total body fat,鈥� Pond explains. 鈥淲hat puzzled me was, why have it sitting right on top of an organ that is moving continuously throughout the animal鈥檚 life, when it would be easy to put another half per cent into the abdomen?鈥� These facts, she says, 鈥渕ade me suspect that storage was, for many of the depots, not the principal function, and might even be a very minor function.鈥�
Small mystery
Pond and her colleague Chris Mattacks began to look for biochemical differences in fat cells in different depots, focusing on the small, hitherto neglected depots in laboratory guinea pigs. 鈥淭hese small depots are metabolically the most interesting,鈥� Pond has shown. Compared to the larger depots, the adipocytes in the small depots are biochemically much more active and they contain less lipid (fat) and much more protein. Moreover, these are the depots that change the least when animals grow fat or thin. What are these small depots up to? Pond wondered.
Pond鈥檚 experiments soon revealed that depots vary in the way they metabolise glucose, absorb lipids or produce key enzymes in response to a meal or a few minutes of exercise. She has also found signs of local interactions between fat cells and their nearest neighbours: evidence to suggest that adipocytes living next to cardiac muscle, for instance, selectively release or take up fatty acids as required by this crucial muscle. Pond began to think that 鈥渢he main job of the adipose tissue in these minor depots out in the periphery is probably as a rationer and a local supplier rather than as an overall energy store. They may moonlight doing that, but it is not their main job.鈥� Their role may be to 鈥渟equester鈥� and release particular nutrients that adjacent tissues use not merely as fuel but as molecular building blocks for cell membranes or chemical messengers.
Pond has now begun to examine the local interactions between fat cells adjacent to lymph nodes 鈥� these local headquarters of the immune system in adult mammals. Although immunology textbooks never remark upon the fact, most lymph nodes are surrounded by at least a small amount of adipose tissue even in seals, where 99 per cent of the animal鈥檚 fatty tissue is present as blubber under the skin.
Fat tricks
Pond suspected that there might well be a good reason for the juxtaposition of immune cells and adipocytes 鈥� two very different kinds of tissue. In ingenious laboratory experiments, she and Mattacks incubated tiny pieces of adipose tissue taken from precise spots in each adipose depot 鈥� with each sample containing about a thousand adipocytes. The fat cells were incubated with white blood cells (lymphocytes) taken from the same healthy adult guinea pig.
What Pond and her colleague found is remarkable. The presence of these small pieces of adipose tissue curtailed the proliferation of lymphocytes that had been stimulated to divide by standard 鈥渕itogenic鈥� chemicals. Two things are particularly striking about these results. First, the fat cells taken from depots that are naturally associated with a lymph node were far more effective at controlling the proliferation of lymphocytes than ones without any nodes 鈥� notably the much-studied perirenal, perched on top of the kidney. Secondly, the adipocytes nearest the node 鈥� those cells that formed a little rind of adipose tissue around it 鈥� had the biggest effect on the lymphocytes. Something released by the fat cells 鈥� probably fatty acids 鈥� seems to influence the process of cell division among these vital components of the immune system, and how effectively they do so depends critically upon exactly where they come from in the guinea pig.
The interaction works both ways. Further experiments have established that adipocytes near lymph nodes selectively respond to the presence of lymphocytes by a four or fivefold increase in the rate at which they release fatty acids. This response is remarkably vigorous given that blood-borne and nerve signals such as adrenaline and insulin normally only produce about a twofold change in fatty acid release.
Yet the big depots without lymph nodes such as the perirenal, the traditional objects of study, do not respond at all. And that is the beauty of the system, Pond suspects. It keeps the response local, supplying the immune cells in a particular spot with the nutrients they need to respond to a neighbourhood callout without involving the entire body in a potentially wasteful, even dangerous, red alert. 鈥淚n a serious infection, the whole system is activated: fever and anorexia set in, which increases the circulating levels of fatty acids. But in little local difficulties you would not need to bother with that.鈥�
This is a novel idea. Standard biochemical thinking has it that adipose tissue simply tips its fatty acids into the blood where everything of interest can be measured; yet the events described by Pond may not be detectable in that way.
The fat cells near the lymph nodes have another trick up their sleeves, Pond suspects; they not only feed immune cells quickly and discreetly, but the food is top quality. Cells of the immune system need long-chain polyunsaturated fatty acids to form new membranes as they proliferate, and to make intercellular messenger molecules 鈥� the cytokines such as interferon. The trouble is, polyunsaturates tend to be in short supply in most mammalian diets (even Flora margarine is only about 10 to 15 per cent polyunsaturates by weight). But Pond鈥檚 work with guinea pigs suggests that the fat cells near the lymph nodes systematically conserve these rare fatty acids, so that the immune system will never run short.
The tiny rind of adipose tissue around the node seems to 鈥渟electively take up and release these fatty acids as and when required to supply its neighbours, the lymph nodes, without making them available to the general public,鈥� Pond explains. 鈥淚f diets are a bit short of the long-chain polyunsaturates, the last thing you want to do is tip them into the bloodstream where other greedy guts tissues like muscle are going to grab hold of them, oxidise them, and then they are gone forever,鈥� argues Pond.
Research by Ren茅 Groscolas at the CNRS Centre for Ecological and Physiological Energetics in Strasbourg suggests a mechanism for Pond鈥檚 findings. Groscolas measured the fatty acids in samples of adipose tissue taken from wild king penguins in Antarctica, before and after their breeding-season fast, which lasts for more than three months in males and reduces their body mass by 40 per cent. Intriguingly, he found that after the fast, the birds鈥� remaining adipose tissue had selectively conserved the rare and valued fatty acids, the long-chained, polyunsaturated ones, and broken down the saturated ones. Groscolas went on to show that adipose tissue in laboratory rats could also perform this feat. Yet for years, biochemists have supposed that the energy-rich triacylglycerol molecules in adipose tissue are broken down at random, regardless of the chemistry of their constituent fatty acids. At least this is what you would expect, if the tissue were just a passive repository.
Pond is accustomed to contesting longstanding 鈥渇acts鈥�: a few years ago, she challenged the textbook dogma that polar bears deposit lots of fat under their skin to keep warm. It鈥檚 their fur that keeps them warm, she has convincingly argued; their fat is there to cope with an erratic food supply, and to tide the females over months of anorexic motherhood. 鈥淚t is mostly under the skin because that is the most convenient place to deposit stores that can be 50 per cent of the total body mass.鈥�
Pond believes that the professional fatties 鈥� wild animals that naturally become obese 鈥� are the best source of clues to the many and varied roles adipose tissue plays. Rats and people are mere novices in the obesity game, compared to many polar animals. Her studies in the Arctic have revealed a whole new world of 鈥渘atural obesity鈥� in which bears, reindeer and arctic foxes combine fatness and fitness, remaining fleet of foot despite a body mass that in the case of the foxes can be 35 per cent fat.
Arctic tales
Pond has spent days in a tent pitched in the Canadian Arctic, dissecting polar bears just hours after they were shot by licensed Inuit hunters, and working quickly to finish before the bears鈥� carcasses froze. She has joined arctic biologists in the remote islands of Svalbard, midway between the north coast of Norway and the North Pole, taking small samples of adipose tissue from arctic foxes and reindeer. Her work has shown that it is possible to work out what the animals have been eating by looking at the composition of their fat. Food is scarce for Svalbard arctic foxes. Their diet, it turns out, varies greatly from area to area, depending on what鈥檚 available. In future work, she hopes to use this technique to monitor the movement of toxic pollutants through the arctic ecosystem; she is convinced that adipose tissue has many stories to tell.
Pond plans to continue both fieldwork on wild animals and laboratory work. One goal is to discover how lymphocytes 鈥渢alk鈥� to the adipocytes 鈥� how they persuade them to request the release of their rare fatty acids; Pond suspects that perhaps one or more of the cytokines does the trick.
Her final message is simple. 鈥淣o single depot can really be taken as representative of the rest.鈥� By and large, the biggest are the most boring metabolically. It is the little depots, virtually ignored until now, that seem to be responding to short term, local needs by selectively dispensing lipids and perhaps amino acids. 鈥淢ost of the adipose depots, most of the time, are doing almost nothing,鈥� says Pond. 鈥淎s in the real world, it is the little guys that are doing the hard work.鈥�