Good Calories, Bad Calories

A single molecule plays the pivotal role in the system. It goes by a number of names, the simplest being glycerol phosphate. This glycerol-phosphate molecule is produced from glucose when it is used for fuel in the fat cells and the liver, and it, too, can be burned as fuel in the cells. But glycerol phosphate is also an essential component of the process that binds three fatty acids into a triglyceride. It provides the glycerol molecule that links the fatty acids together.^†116 In other words, a product of carbohydrate metabolism—i.e., burning glucose for fuel—is an essential component in the regulation of fat metabolism: storing fat in the fat tissue. In fact, the rate at which fatty acids are assembled into triglycerides, and so the rate at which fat accumulates in the fat tissue, depend primarily on the availability of glycerol phosphate. The more glucose that is transported into the fat cells and used to generate energy, the more glycerol phosphate will be produced. And the more glycerol phosphate produced, the more fatty acids will be assembled into triglycerides. Thus, anything that works to transport more glucose into the fat cells—insulin, for example, or rising blood sugar—will lead to the conversion of more fatty acids into triglycerides, and the storage of more calories as fat.

This brings us to the mechanisms that control and regulate the availability of fat and carbohydrates for fuel and regulate our blood sugar in the process.

The first is the triglyceride/fatty-acid cycle we just discussed. This cycle is regulated by the amount of blood sugar made available to the fat tissue. If blood sugar is ebbing, the amount of glucose transported into the fat cells will decrease; this limits the burning of glucose for energy, which in turn reduces the amount of glycerol phosphate produced. With less glycerol phosphate present, fewer fatty acids are bound up into triglycerides, and more of them remain free to escape into the circulation. As a result, the fatty-acid concentration in the bloodstream increases. The bottom line: as the blood-sugar level decreases, fatty-acid levels rise to compensate.

If blood-sugar levels increase—say, after a meal containing carbohydrates—then more glucose is transported into the fat cells, which increases the use of this glucose for fuel, and so increases the production of glycerol phosphate. This is turn increases the conversion of fatty acids into triglycerides, so that they’re unable to escape into the bloodstream at a time when they’re not needed. Thus, elevating blood sugar serves to decrease the concentration of fatty acids in the blood, and to increase the accumulated fat in the fat cells.

The second mechanism that works to regulate the availability of fuel and to maintain blood sugar at a healthy level is called the glucose/fatty-acid cycle, or the Randle cycle, after the British biochemist Sir Philip Randle. It works like this: As blood-sugar levels decrease—after a meal has been digested—more fatty acids will be mobilized from the fat cells, as we just discussed, raising the fatty-acid level in the bloodstream. This leads to a series of reactions in the muscle cells that inhibit the use of glucose for fuel and substitute fatty acids instead. Fatty acids generate the necessary cellular energy, and the blood-sugar level in the circulation stabilizes. When the availability of fatty acids in the blood diminishes, as would be the case when blood-sugar levels are rising, the cells compensate by burning more blood sugar. So increasing blood-sugar levels decreases fatty-acids levels in the bloodstream, and decreasing fatty-acid levels in the bloodstream, in turn, increases glucose use in the cells. Blood- sugar levels always remain within safe limits—neither too high nor too low.

These two cycles are the fundamental mechanisms that maintain and ensure a steady fuel supply to our cells. They provide a “metabolic flexibility” that allows us to burn carbohydrates (glucose) when they’re present in the diet, and fatty acids when they’re not. And it’s the cells of the adipose tissue that function as the ultimate control mechanism of this fuel supply.

Regulation by hormones and the nervous system is then layered onto these baseline mechanisms to deal with the vagaries of the external environment, providing the moment-to-moment and season-to-season fine-tuning necessary for the body to work at maximum efficiency. Hormones modify this flow of fatty acids back and forth across the membranes of the fat cells, and they modify the expenditure of energy by the tissues and organs. Hormones, and particularly insulin—“even in trace amounts,” as Ernst Wertheimer explained—“have powerful direct effect on adipose tissue.”

With the invention by Rosalyn Yalow and Solomon Berson of their radioimmunoassay to measure insulin levels, it quickly became clear that insulin was what Yalow and Berson called “the principal regulator of fat metabolism.” Insulin stimulates the transport of glucose into the fat cells, thereby effectively controlling the production of glycerol phosphate, the fixing of free fatty acids as triglycerides, and all that follows. The one fundamental requirement to increase the flow of fatty acids out of adipose tissue—to increase lipolysis—and so decrease the amount of fat in our fat tissue, is to lower the concentration of insulin in the bloodstream. In other words, the release of fatty acids from the fat cells and their diffusion into the circulation require “only the negative stimulus of insulin deficiency,” as Yalow and Berson wrote. By the same token, the one necessary requirement to shut down the release of fat from the fat cells and increase fat accumulation is the presence of insulin. When insulin is secreted, or the level of insulin in the circulation is abnormally elevated, fat accumulates in the fat tissue. When insulin levels are low, fat escapes from the fat tissue, and the fat deposits shrink.

All other hormones will work to release fatty acids from the fat tissue, but the ability of these hormones to accomplish this job is suppressed almost entirely by the effect of insulin and blood sugar. These hormones can mobilize fat from the adipose tissue only when insulin levels are low—during starvation, or when the diet being consumed is lacking in carbohydrates. (If insulin levels are high, that implies that there is plenty of carbohydrate fuel available.) In fact, virtually anything that increases the secretion of insulin will also suppress the secretion of hormones that release fat from the fat tissue. Eating carbohydrates, for example, not only elevates insulin but inhibits growth-hormone secretion; both effects lead to greater fatty-acid storage in the fat tissue.

Hormones that promote fat mobilization

Hormones that promote fat accumulation

Epinephrine

Norepinephrine

Adrenocorticotropic hormone (ACTH)

Glucagon

Thyroid-stimulating hormone

Insulin

Melanocyte-stimulating hormone

Vasopressin

Growth hormone

In 1965, hormonal regulation of adipose tissue looked like this: at least eight hormones that worked to release fat from the adipose tissue and one, insulin, that worked to put it there.

That increasing the secretion of insulin can in fact cause obesity (i.e., excess fat accumulation) would be demonstrated conclusively in animal models of obesity, particularly in the line of research we discussed in Chapter 21 on rats and mice with lesions in the area of the brain known as the ventromedial hypothalamus, or VMH. In the 1960s, this research became another beneficiary of Yalow and Berson’s new technology to measure circulating