快猫短视频

THEY are unbelievably rude. Not content with staring and pointing, many people call their friends over to join in the gawping. Some even follow you around. Dealing with these kinds of reactions because you look different is hard enough for an adult, but for a teenager like 14-year-old Elisha^* it can be extremely distressing. She stands out from the crowd because she was born without any body fat.

Many of us grappling with expanding waistlines may think that having no body fat sounds like a great idea. But the reality is very different. An absence of the fat tissue that most of us are only too eager to wish away causes great suffering for people like Elisha, who has a rare genetic condition called Berardinelli-Seip syndrome.

快猫短视频s researching this condition have recently made discoveries that should soon make life a lot easier for patients like Elisha. And in an ironic twist, their work will also help people who are obese, too.

Berardinelli-Seip syndrome is one of many forms of lipodystrophy, a total or partial loss of body fat. You can be born with lipodystrophy or acquire it later in life 鈥� people infected with HIV often develop it. Lipodystrophy highlights what most of us do not appreciate: that our body fat is in fact an important body organ that plays a vital role in keeping us healthy. The strange thing is that having too little fat can cause the same kinds of health problems as having too much.

The most obvious outward symptom of lipodystrophy is the change it makes to your appearance: 鈥渓ooking different and being bony and muscly and stuff鈥�, as Elisha puts it. The loss of fat from under the skin, which normally smoothes out the contours of the face and body, and the overdevelopment of muscles can make people appear gaunt and masculine, which is especially distressing for women and girls. Another problem is hormone disruption. This can make a child grow unusually tall and develop characteristic facial features, such as a prominent jaw.

Then there is the constant hunger. Normally, body fat helps regulate appetite by making a hormone called leptin. Without leptin, the body thinks it is always starving, even after meals. Elisha鈥檚 mother, Helen^* often caught her young daughter raiding the kitchen cupboards. 鈥淥ne of the doctors explained it was like an addict looking for a fix,鈥� she says. 鈥淭hat was quite a difficult time.鈥�

Lacking storage space for fat, lipodystrophy patients often have high levels of fats in their blood and an incidence of heart disease a hundred fold higher than that of the general population.

快猫短视频s researching lipodystrophy have come up with ways of treating some of its symptoms. Careful control of diet can help. And Elisha is now taking part in a trial where she receives injections of leptin, with the aim of curbing her hunger and some of her other symptoms and the results are encouraging.

But the researchers have also uncovered an intriguing aspect of lipodystrophy that at first seems bizarre and ironic. Lipodystrophy patients all develop type 2 diabetes, the same condition that is caused by obesity. (Type 1 diabetes, in contrast, is the kind caused by the immune system destroying the pancreatic cells that produce insulin, the hormone that tells cells all over the body to absorb glucose from the blood.)

This does not seem to make sense. How can having no fat produce the same disease as having too much? It turns out that some of our old ideas about what type 2 diabetes really is were wrong.

The underlying problem in type 2 diabetes is 鈥渋nsulin resistance鈥� which means that a person鈥檚 cells no longer respond as well to insulin鈥檚 command to absorb glucose. When this happens, glucose builds up in the bloodstream and can cause a whole host of problems including blindness, kidney failure and nerve damage.

Given diabetic patients鈥� high blood sugar levels, it is unsurprising that scientists originally believed that type 2 diabetes was a disease of carbohydrate metabolism. Not any more. There is now good evidence that what appears to be a carbohydrate problem is really a fat problem in disguise. If your body cannot store fat properly, either because it has nowhere to go, as in lipodystrophy patients, or because the storage depots are overwhelmed, as in obese patients, it deafens the body鈥檚 ability to hear insulin鈥檚 signal. Researchers call it lipotoxicity: literally, fat poisoning.

This view explains why overindulgence makes type 2 diabetes more likely. It also suggests new ways of treating the condition. And we desperately need those (see Map). By some estimates, a quarter of a billion people worldwide will be coping with type 2 diabetes by 2020, largely as a result of the growing epidemic of obesity and the ageing population.

Much of these new insights into diabetes come from the study of lipodystrophy. 鈥淭here was a saying when I was in medical school that the rare bird can teach you about the common,鈥� says Robert Hegele, an endocrinologist at the Robarts Research Institute in London, Ontario, who treats people with lipodystrophy. Unable to store fat in the usual way, their bodies shunt it into muscle tissue or the liver, where it begins to cause problems. And the same process happens in obese people.

Much as we may dislike it, adipose tissue, or body fat, is our friend, from a metabolic point of view. It carves up the fat we eat into fragments called fatty acids and stores them out of harm鈥檚 way until needed.

But adipose tissue is no bottomless pit. If we overindulge, its storage capacity becomes overwhelmed and fatty acids end up spilling over into muscle cells, just as they do in people with lipodystrophy. Elisha has to stick to a very low-fat diet to keep symptoms to a minimum.

When fatty acids or their breakdown products accumulate in muscle, they trigger insulin resistance. 鈥淭hat鈥檚 why virtually all obese individuals are insulin resistant,鈥� says Gerald Shulman, an endocrinologist at the Howard Hughes Medical Institute at Yale University. He singles out muscle not because all the excess fat ends up there 鈥� much also goes to the liver and other organs 鈥� but because muscle tissue is the heaviest user of glucose from the bloodstream, and thus is the place where insulin resistance has its biggest impact in the progression toward type 2 diabetes.

Through a series of experiments over the past few years, Shulman and others are beginning to understand the intricate molecular dance by which this occurs. Normally, insulin binds to a receptor on the surface of muscle cells. This triggers a cascade of signals that activate the cell鈥檚 various responses to insulin. The most important of these is to shift glucose-transporter molecules from storage depots within the cell to the outer membrane, where they can import glucose.

Poison

In people who are obese, and perhaps those with lipodystrophy, excess fatty acids poison this process in several ways. 鈥淚t鈥檚 a multi-hit process. I don鈥檛 think we can identify one single defect in the origin of insulin resistance,鈥� says Hari Hundal, a molecular physiologist at the University of Dundee in the UK.

One key step, though, is that muscle cells convert fatty acids into a related molecule called ceramide, and excess fatty acids mean more ceramide. Hundal and his colleagues have shown that ceramide interferes with a signalling molecule that helps glucose transporters move to the cell surface. It also activates other molecules that block the relay of the insulin signal inside the cell.

Ceramide may advance the progress of type 2 diabetes in another important way. It appears to kill off insulin-producing cells in the pancreas. In the early stages of insulin resistance, these cells compensate for insulin鈥檚 dwindling potency by simply churning out more of the stuff, to try to keep blood glucose normal. But ceramide forces pancreatic cells to activate their self-destruct programme, according to experiments in mice by Roger Unger, a diabetologist at the University of Texas Southwestern Medical Center in Dallas. This erodes the organ鈥檚 ability to produce insulin. Many people with long-standing type 2 diabetes end up both insulin resistant and lacking the ability to produce normal levels of insulin. Ceramide only had this effect, however, if Unger also blocked the action of the appetite-regulating hormone leptin, which would otherwise keep ceramide from doing harm. Many researchers suspect that defects in leptin signalling are common in obese people.

Importantly for those trying to eat healthily, only saturated fatty acids, the ones usually found in animal fat, can be converted into ceramide. The monounsaturated fatty acids found in olive oil or the polyunsaturates in canola oil cannot. This helps explain why a diet rich in animal fats causes more health problems than one high in unsaturated vegetable fats. Hundal is not ready to let unsaturated fats off the hook entirely, though. Both saturated and unsaturated fatty acids can be converted to another molecule called diacylglycerol, which has also been shown to interfere with insulin signalling. 鈥淪ome fats are worse than others, but you鈥檝e still got to watch the level of fat you take in,鈥� he says.

Lipodystrophy or a fatty diet are not the only reason fatty acids can accumulate in muscle tissue. Defects in mitochondria 鈥� the power generators inside cells that burn fatty acids as fuel 鈥� may play a key role, as well. In February, Shulman鈥檚 group reported that lean, insulin-resistant people with a family history of type 2 diabetes had mitochondrial function about 30 per cent lower than otherwise similar, insulin-sensitive people. So an inability to use up fatty acids could also play a part in insulin resistance. The well-documented tendency for mitochondria to accumulate damage over the years may explain why insulin resistance is such a frequent companion to ageing, Shulman thinks. And inherited differences in mitochondrial activity may also help explain why some people are more susceptible to type 2 diabetes than others.

All of this focuses on the trouble fatty acids cause by themselves, but some researchers think that adipose tissue plays a much more important role than just keeping fatty acids from spilling over into other tissues. 鈥淭hat鈥檚 a very passive role for the fat cell 鈥� it鈥檚 just a tank,鈥� says Mitchell Lazar, director of the diabetes centre at the University of Pennsylvania in Philadelphia. Instead, he thinks fat cells take a more active part in directing insulin sensitivity in the rest of the body. After all, he notes, a major class of insulin-sensitising drugs 鈥� thiazolidinediones, or TZDs 鈥� act by stimulating a receptor found mostly in the nucleus of fat cells.

This new understanding of how fat poisons the body鈥檚 response to insulin and how insulin resistance develops is fuelling the development of new drugs that could help lipodystrophy patients and obese diabetic patients alike. For instance, several different biochemical pathways inside a cell can affect how it responds to insulin. Find the enzymes involved and you have got a new set of drug targets. Other drugs might block the conversion of fatty acids to ceramide.

An even more promising target is an enzyme known as AMP kinase, or AMPK. Sometimes called the cell鈥檚 fuel gauge, AMPK helps recharge a cell鈥檚 battery when it runs low by telling the cell to start burning more glucose and fatty acids. One effect of this is to reduce fatty acid concentrations within the cell, and sure enough, when AMPK is activated muscle cells become more sensitive to insulin. Exercise, because it depletes the cell鈥檚 fuel, gives a natural boost to AMPK activity. 鈥淲e suggest that AMPK is very much involved in the health benefits of exercise,鈥� says Grahame Hardie, of the University of Dundee. Metformin, a commonly used anti-diabetic drug, works at least in part by stimulating AMPK, and several major pharmaceutical companies are looking for better drugs to do the same. These could be the equivalent of exercise in a pill. Medically useful, to be sure, but likely to fall short of the comprehensive benefits of the real thing.

Drugs that boost a cell鈥檚 ability to deal with fatty acids could help people like Elisha too. Although treatment with leptin can go a long way to reducing symptoms such as insatiable appetite and high blood sugar, it is not a complete cure. Lipodystrophy patients will probably also need drugs such as metformin to fully control their metabolic disease.

Lipodystrophy has given scientists a window on the key role body fat plays in our health and highlighted new drug targets to help when it goes wrong. But although such drugs could treat the metabolic symptoms of lipodystrophy or obesity, they will not fix the cosmetic or social aspects of these conditions. Science has yet to find a cure for bad manners and prejudice. 鈥淵ounger people you could sort of understand why they are a bit sort of weird,鈥� says Elisha, 鈥渂ut older people 鈥� they should know better.鈥�

^*Names have been changed

Additional reporting by Claire Ainsworth