Good Calories, Bad Calories (71 page)

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 cel s wil 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 cel s, 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 cel s.

The second mechanism that works to regulate the availability of fuel and to maintain blood sugar at a healthy level is cal ed 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 wil be mobilized from the fat cel s, as we just discussed, raising the fatty-acid level in the bloodstream. This leads to a series of reactions in the muscle cel s that inhibit the use of glucose for fuel and substitute fatty acids instead. Fatty acids generate the necessary cel ular 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 cel s 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 cel s. 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 cel s. They provide a “metabolic flexibility” that al ows us to burn carbohydrates (glucose) when they’re present in the diet, and fatty acids when they’re not. And it’s the cel s 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 cel s, 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 cal ed “the principal regulator of fat metabolism.” Insulin stimulates the transport of glucose into the fat cel s, thereby effectively control ing the production of glycerol phosphate, the fixing of free fatty acids as triglycerides, and al that fol ows. 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 cel s 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 cel s and increase fat accumulation is the presence of insulin. When insulin is secreted, or the level of insulin in the circulation is abnormal y elevated, fat accumulates in the fat tissue. When insulin levels are low, fat escapes from the fat tissue, and the fat deposits shrink.

Al other hormones wil 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, virtual y anything that increases the secretion of insulin wil 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 levels of insulin. As investigators now reported, insulin secretion in VMH-lesioned animals increases dramatical y within seconds of the surgery. The insulin response to eating also goes “off the scale” with the very first meal. The more insulin secreted in the days after the surgery, the greater the ensuing obesity. Obesity in these lesioned animals could be prevented by short-circuiting the exaggerated insulin response—by severing the vagus nerve, for example, that links the hypothalamus with the pancreas.*117 Similarly, the hypersecretion of insulin was reported to be the earliest detectable abnormality in genetic strains of obesity-prone mice and rats.

By the mid-1970s, it was clear that Stephen Ranson’s insights into obesity in these animals had been confirmed. The lesion causes a defect in the part of the hypothalamus that regulates what researchers have come to cal fuel partitioning—the result is the hypersecretion of insulin. The insulin forces the accumulation of fat in the fat tissue, and the animal overeats to compensate. This research refuted John Brobeck’s notion, which has since become the standard wisdom in the field, that the VMH lesion causes overeating directly and the animals grow fat simply because they eat too much. These studies were neither ambiguous nor controversial. In 1976, University of Washington investigators Stephen Woods and Dan Porte described as “overwhelming”

the evidence that the increased secretion of insulin is the primary effect of VMH lesions, the driving force of obesity in these animals.

This half century of research unequivocal y supported the alternative hypothesis of obesity. It established that the relevant energy balance isn’t between the calories we consume and the calories we expend, but between the calories—in the form of free fatty acids, glucose, and glycerol—passing in and out of the fat cel s. If more and more fatty acids are fixed in the fat tissue than are released from it, obesity wil result. And while this is happening, as Edgar Gordon observed, the energy available to the cel s is reduced by the “relative unavailability of fatty acids for fuel.” The consequence wil be what Stephen Ranson cal ed semi-cellular starvation and Edwin Astwood, twenty years later, cal ed internal starvation. And as this research had now made clear, the critical molecules determining the balance of storage and mobilization of fatty acids, of lipogenesis and lipolysis, are glucose and insulin—i.e., carbohydrates and the insulin response to those carbohydrates.

Just a few more details are necessary to understand why we get fat. The first is that the amount of glycerol phosphate available to the fat cel s to accumulate fat—to bind the fatty acids together into triglycerides and lock them into the adipose tissue—also depends directly on the carbohydrates in the diet. Dietary glucose is the primary source of glycerol phosphate. The more carbohydrates consumed, the more glycerol phosphate available, and so the more fat can accumulate. For this reason alone, it may be impossible to store excess body fat without at least some carbohydrates in the diet and without the ongoing metabolism of these dietary carbohydrates to provide glucose and the necessary glycerol phosphate.

“It may be stated categorical y,” the University of Wisconsin endocrinologist Edgar Gordon wrote in JAMA in 1963, “that the storage of fat, and therefore the production and maintenance of obesity, cannot take place unless glucose is being metabolized. Since glucose cannot be used by most tissues without the presence of insulin, it also may be stated categorical y that obesity is impossible in the absence of adequate tissue concentrations of insulin…. Thus an abundant supply of carbohydrate food exerts a powerful influence in directing the stream of glucose metabolism into lipogenesis, whereas a relatively low carbohydrate intake tends to minimize the storage of fat.”

Forty years ago, none of this was controversial—and the facts have not changed since then. Insulin works to deposit calories as fat and to inhibit the use of that fat for fuel. Dietary carbohydrates are required to al ow this fat storage to occur. Since glucose is the primary stimulator of insulin secretion, the more carbohydrates consumed—or the more refined the carbohydrates—the greater the insulin secretion, and thus the greater the accumulation of fat.

“Carbohydrate is driving insulin is driving fat,” as the Harvard endocrinologist George Cahil recently summed it up.

Regarding the potential dangers of sugar in the diet, it is important to keep in mind that fructose is converted more efficiently into glycerol phosphate than is glucose. This is another reason why fructose stimulates the liver so readily to convert it to triglycerides, and why fructose is considered the most lipogenic carbohydrate. Fructose, however, does not stimulate the pancreas to secrete insulin, so glucose is stil needed for that purpose. This suggests that the combination of glucose and fructose—either the 50–50 mixture of table sugar (sucrose) or the 55–45 mixture of high-fructose corn syrup

—stimulates fat synthesis and fixes fat in the fat tissue more than does glucose alone, which comes from the digestion of bread and starches.

It is important also to know that the fat cel s of adipose tissue are “exquisitely sensitive” to insulin, far more so than other tissues in the body. This means that even low levels of insulin, far below those considered the clinical symptom of hyperinsulinemia (chronical y high levels of insulin), wil shut down the flow of fatty acids from the fat cel s. Elevating insulin even slightly wil increase the accumulation of fat in the cel s. The longer insulin remains elevated, the longer the fat cel s wil accumulate fat, and the longer they’l go without releasing it.

Moreover, fat cel s remain sensitive to insulin long after muscle cel s become resistant to it. Once muscle cel s become resistant to the insulin in the bloodstream, as Yalow and Berson explained, the fat cel s have to remain sensitive to provide a place to store blood sugar, which would otherwise either accumulate to toxic levels or overflow into the urine and be lost to the body. As insulin levels rise, the storage of fat in the fat cel s continues, long after the muscles become resistant to taking up any more glucose. Nonetheless, the pancreas may compensate for this insulin resistance, if it can, by secreting stil more insulin. This wil further elevate the level of insulin in the circulation and serve to increase further the storage of fat in the fat cel s and the synthesis of carbohydrates from fat. It wil suppress the release of fat from the fat tissue. Under these conditions—lipid trapping, as the geneticist James Neel described it—obesity begins to look preordained. Weights wil plateau, as Dennis McGarry suggested in Science in 1992, only when the fat tissue becomes insulin-resistant as wel , or when the fat deposits enlarge to the point where the forces working to release the fat and burn it for fuel—such as the increased concentration of fatty acids inside the fat cel s—once again balance out the effect of the insulin itself.

By the mid-1960s, four facts had been established beyond reasonable doubt: (1) carbohydrates are singularly responsible for prompting insulin secretion; (2) insulin is singularly responsible for inducing fat accumulation; (3) dietary carbohydrates are required for excess fat accumulation; and (4) both Type 2

diabetics and the obese have abnormal y elevated levels of circulating insulin and a “greatly exaggerated” insulin response to carbohydrates in the diet, as was first described in 1961 by the Johns Hopkins University endocrinologists David Rabinowitz and Kenneth Zierler.

The obvious implication is that obesity and Type 2 diabetes are two sides of the same physiological coin, two consequences, occasional y concurrent, of the same underlying defects—hyperinsulinemia and insulin resistance. This was precisely what von Noorden had suggested in 1905 with his diabetogenous-obesity hypothesis, even down to the notion that obesity would natural y result when muscle tissue becomes resistant to taking up glucose from the circulation before fat tissue does. Now the science had caught up to the speculation. “We general y accept that obesity predisposes to diabetes; but does not mild diabetes predispose to obesity?” as Yalow and Berson wrote in 1965. “Since insulin is a most lipogenic agent, chronic hyperinsulinism would favor the accumulation of body fat.”