metabolism is shifted in the direction of storage away from oxidation?” Why is fat deposited in the adipose tissue to accumulate in excess of its mobilization for fuel use? Once again, this has little to do with calories consumed or expended, but addresses the questions of how the cells utilize these calories and how the body regulates its balance between fat deposition and mobilization, between lipogenesis (the creation of fat) and lipolysis (the breakdown of triglycerides into fatty acids, their escape from the fat tissue, and their subsequent use as fuel). “Since it is now assumed that the genes and enzymes are closely associated,” Bruch wrote in 1957, “it is conceivable that people with the propensity for fat accumulation have been born with enzymes that are apt to facilitate the conversion of certain reactions in that direction.”
The third phase of this research finally established the dominant role of fatty acids in supplying energy for the body, and the fundamental role of insulin and adipose tissue as the regulators of energy supply. As early as 1907, the German physiologist Adolf Magnus-Levy had noted that during periods of fasting between meals “the fat streams from the depots back again into the blood…as if it were necessary for the immediate needs of the combustion processes of the body.” A decade later, Francis Benedict reported that blood sugar provides only a “small component” of the fuel we use during fasting, and this drops away to “none at all” if our fast continues for more than a week. In such cases, fat will supply 85 percent of our energy needs, and protein the rest, after its conversion to glucose in the liver. Still, because the brain and central nervous system typically burn 120 to 130 grams of glucose a day, nutritionists insisted (as many still do) that carbohydrates must be our primary fuel, and they remained skeptical of the notion that fat plays any role in energy balance other than as a long-term reserve for emergencies.
Among physiologists and biochemists, any such skepticism began to evaporate after Wertheimer’s review of fat metabolism appeared in 1948. It vanished after the 1956 publication of papers by Vincent Dole at Rockefeller University, Robert Gordon at NIH, and Sigfrid Laurell of the University of Lund in Sweden that reported the development of a technique for measuring the concentration of fatty acids in the circulation. All three articles suggested that these fatty acids were the form in which fat is burned for fuel in the body. The concentration of fatty acids in the circulation, they reported, is surprisingly low immediately after a meal, when blood-sugar levels are highest, but then increases steadily in the hours that follow, as the blood sugar ebbs. Injecting either glucose or insulin into the circulation diminishes the level of fatty acids almost immediately. It’s as though our cells have the option of using fatty acids or glucose for fuel, but when surplus glucose is available, as signaled by rising insulin or blood-sugar levels, the fatty acids are swept into the fat tissue for later use. The concentration of circulating fatty acids rises and falls in “relation to the need” for fuel, wrote Gordon. And because injections of adrenaline cause a flooding of the circulation with fatty acids, and because adrenaline is naturally released by the adrenal glands as an integral part of the flight-fight response, Gordon suggested that the concentration of fatty acids also rises in relation to “the anticipated need” for fuel.
In 1965, the American Physiological Society published an eight-hundred-page
Since the excessive accumulation of fat in the fat tissue is the problem in obesity, we need to understand this primary control mechanism. This means, first of all, that we have to appreciate the difference between triglycerides and free fatty acids. They’re both forms fat takes in the human body, but they play very different roles, and these are tied directly to the way the oxidation and storage of fats and carbohydrates are regulated.
When we talk about the fat stored in the adipose tissue or the fats in our food, we’re talking about triglycerides. Oleic acid, the monounsaturated fat of olive oil, is a fatty acid, but it is present in oils and meats in the form of a triglyceride. Each triglyceride molecule is composed of three fatty acids (the “tri”), linked together on a backbone of glycerol (the “glyceride”). Some of the triglycerides in our fat tissue come from fat in our diet. The rest come from carbohydrates, from a process known as de novo lipogenesis, which is Latin for “the new creation of fat,” a process that takes place both in the liver and, to a lesser extent, in the fat tissue itself. The more carbohydrates flooding the circulation after a meal, the more will be converted to triglycerides and stored as fat for future use (perhaps 30 percent of the carbohydrates in any one meal). “This lipogenesis is regulated by the state of nutrition,” explained Wertheimer in an introductory chapter to the
A second critical point is that while the fat is stored as triglycerides it enters and exits the fat cells in the form of fatty acids—actually, free fatty acids, to distinguish them from the fatty acids bound up in triglycerides—and it’s these fatty acids that are burned as fuel in the cells. As triglycerides, the fat is locked into the fat cells, because triglycerides are too big to slip through the cell membranes. They have to be broken down into fatty acids—the process technically known as lipolysis—before the fat can escape into the circulation. The triglycerides in the bloodstream must also be broken down into fatty acids before the fat can diffuse into the fat cells. It’s only reconstituted into triglycerides, a process called esterification, once the fatty acids have passed through the walls of the blood vessels and the fat-cell membranes and are safely inside. This is true for all triglycerides, whether they originated as fat in the diet or were converted from carbohydrates in the liver.
Inside the fat cells, triglycerides are continuously broken down into their component fatty acids and glycerol (i.e., in lipolysis), and fatty acids and glycerol are continuously reassembled into triglycerides (i.e., esterified)—a process known as the triglyceride/fatty-acid cycle. Any fatty acids that are not immediately repackaged back into triglycerides will slip out of the fat cell and back into the circulation—“a ceaseless stream of [free fatty acids], a readily transportable source of energy, into the bloodstream,” as it was described in the
Some of these free fatty acids will be taken up by the tissues and organs and used as fuel. Perhaps as much as half of them will not. These will be incorporated in the liver back into triglycerides, loaded on lipoproteins,*115 and shipped back again to the fat tissue. And so fatty acids are continuously slipping from the fat tissue into the circulation, while those fatty acids that aren’t immediately taken up and used for fuel are continuously being reconverted to triglycerides and transported back to the fat tissue for storage. “The storage of triglyceride fat in widely scattered adipose tissue sites is a remarkably dynamic process,” explained the University of Wisconsin endocrinologist Edgar Gordon in 1969, “with the stream of fatty acid carbon atoms flowing in widely fluctuating amounts, first in one direction and then the other in a finely adjusted minute by minute response to the fuel requirements of energy metabolism of the whole organism.”
This remarkably dynamic process, however, is regulated by a remarkably simple system. The flow of fatty acids out of the fat cells and into the circulation depends on the level of blood sugar available. The burning of this blood sugar by the cells—the oxidation of glucose—depends on the availability of fatty acids to be burned as fuel instead.
