Energy Metabolism and Biochemistry of Obesity

| June 2, 2007

by Sayeed Ikramuddin, MD; Daniel Leslie, MD; Bryan A. Whitson, MD; and Todd A. Kellogg, MD, PhD

All from the University of Minnesota Medical Center in Minneapolis, Minnesota.

This article serves as an update of an article on the same topic published in Bariatric Times in September, 2005. (Ikramuddin S, Kellogg, TA. Energy Metabolism and Biochemistry of Obesity. Bariatric Times 2005;(2)5:37–9)


Obesity, though clearly a result of energy excess in comparison to energy expenditure, has been difficult to establish as a disease. It is true that obesity is now occurring at epidemic proportions. In parallel, efforts to treat obesity are increasing. Currently, surgery is the only proven treatment resulting in sustained weight loss for the morbidly obese.[1] It is important to stress that surgery alone is not effective; however, surgery in a program of behavioral modification and sustained caloric reduction results in sustained weight loss greater than five years.

It is no wonder that investigators are using bariatric surgical techniques as models to try to ascertain the mechanism of massive weight loss and improvement of type 2 diabetes (T2DM). In turn, these observations can yield important new targets for non surgical or medical interventions for the treatment of morbid obesity. We learn more about the mechanisms of morbid obesity every day; however, though an estimated 150,000 bariatric procedures are performed annually, we still have a great deal to learn.[2] As we continue to understand the mechanisms of morbid obesity, it still appears that there is a complex interplay between the brain, the stomach, the hindgut, the foregut, and the sympathetic and parasympathetic nerves that interact and connect these centers.

The Central Nervous System

Chief among the centers of the brain is the ventral hypothalamus. The ventral hypothalamus serves as the central organizing area that controls eating behaviors. A key area of the ventral hypothalamus is the arcuate nucleus. The arcuate nucleus contains two opposing sets of neurons: those that, when activated, will stimulate appetite (orexigenic), and those that, when stimulated, will decrease appetite (anorexigenic). The former include the agouti-related peptide (AgRP) and neuropeptide Y (NPY) neurons. Stimulation causes an increase in appetite and a decrease in metabolism through antagonism of melanocyte stimulating hormones (MSH). These hormones are stimulated by ghrelin and inhibited by leptin as well as peptide YY (PYY). The opposing neurons include the pro-opiomelanocortin (POMC) and cocaine amphetamine regulated transcript neurons (CART). POMC is cleaved to alpha MSH, which in turn stimulates anorexigenic hormones. These hormones in the hypothalamus will decrease appetite and increase energy conservation. Secondary neurons from these sites then feed to the nucleus tractus solitarius (NTS), which influences eating behaviors through a variety of mechanisms, including the sympathetic nervous system.[3,4] In patients who are morbidly obese, there appears to be impairment in the sympathetic nervous system.[4,5]

These centers in the brain are acted upon by substances also produced from both fat and the gastrointestinal tract.

Figure 1


Adipocytes produce cytokines, such as tumor necrosis factor alpha (TNFa), resistin, leptin, adiponectin, and Acpr30 (adipocyte complement-related protein of 30 kDa), all of which have profound effects to varying degrees in the central nervous system to influence metabolism.[7] Aside from the gut, the adipocyte is a powerful mediator of obesity. Understanding of adipocyte biology is probably 10 years behind that of the endothelial cell. The fat cell is equally, if not more, complex. Originally, the adipocyte was thought of as a passive storage depot for fat, and that there were a fixed number. Today there is evidence to suggest that the number of adipocytes can increase in number based on obesity. When the obesity decreases, the adipocytes can potentially differentiate, although the evidence for this is still somewhat inconclusive.


Adiponectin is secreted by adipocytes and is a mediator of insulin sensitivity, is protective, and has anti-inflammatory effects. Plasma adiponectin concentration in obese patients is decreased in comparison to non obese patients. In many previous studies, the postoperative levels of adiponectin after gastric bypass have been shown to increase at 6 and 12 months.[7-10]


The first anorexigenic hormone to be identified was leptin. Leptin is a product of the OB gene that was first identified in mice. Leptin has been found to suppress NPY neurons in the hypothalamus. Mice that are genetically deficient in leptin (OB/OB gene) are found to be morbidly obese.[3] The word leptin is derived from the Greek word leptos, meaning thin. There have been very few reported human cases of leptin deficiency and this defect is not a significant contributor to obesity in humans. There are only rare monogenic causes of obesity related to either leptin deficiency or deficiency of the leptin receptor. Those related to leptin deficiency are associated with a family of South Asian origin who were extremely obese and responded very well to recombinant leptin. Somewhat paradoxically, leptin is positively correlated with total body fat and stimulates satiety and increased energy expenditure.[25, 26]

Figure 2

Defects in the leptin receptor have also been identified with patients presenting with insulin resistance, amenorrhea, and other endocrine problems. Today it is felt that leptin is chiefly involved in long-term regulation of obesity, and its role in short-term obesity is thought to be less important.[6] Leptin levels following the Roux-en-Y gastric bypass will drop.[7,17,27] This postoperative drop in leptin may signify a decrease in leptin resistance. Leptin receptors are located on pancreatic beta cells resulting in decreased insulin production when

Resistin contributes to insulin insensitivity and plasma resistin concentration correlates with the level of insulin resistance.[11] Resistin has been shown to be markedly elevated in the morbidly obese population, compared to non-obese individuals.2 However, the data evaluating the comparison of resistin and the T2DM status are conflicting. In a study of 45 T2DM and 34 non-diabetic patients, the resistin levels of the diabetics were approximately 20 percent higher than the non-diabetic patients.[12] This elevation has not been seen universally. In a study of 12 T2DM and 77 non-diabetic controls, there was no association of resistin and diabetic status.[13] Data in the literature comparing the combination of obese individuals and diabetic status with postoperative changes are lacking. Data available describe changes evident in the postoperative response of obese patients in general. Vendrell and colleagues showed no correlation of resistin levels comparing preoperative to postoperative status.[2] The reasons for the disparate resistin results in unknown but perhaps is due to overlapping feedback control mechanisms. Vendrell also found that resistin was correlated to BMI, fat-free mass, weight, and tumor necrosis factor receptor.[2,29]

TNFa is also associated with insulin resistance in the morbidly obese.[33] Hyperglycemia in T2DM causes increased TNFa levels and associated immune activation.[14] Molina and colleagues indirectly followed the TNFa system by following the TNF receptor postoperatively and found a transient increase in the receptor level at one month postoperatively which then decreased and remained relatively constant at later time points postoperatively.[15] Vazquez and colleagues followed the plasma TNFa levels and found that compared to non-obese controls, obese patients had elevated levels of TNFa, which did not decrease significantly after bariatric surgery.[16]

The Gut

There are over 20 known messengers that are produced by the gut. Considerable interest now surrounds the hormone known as ghrelin. Ghrelin is an orexigenic hormone that is produced by the stomach, pancreas and probably the proximal portion of the small intestine. It was identified by a group looking for a growth hormone releasing hormone analogue. Ghrelin is known as the “hunger hormone” and is responsible for meal initiation.[8] Its levels will rise just before a meal and will decrease after eating. It was once thought that the response to a small meal was attenuated in obese patients compared to others; however, when the octanoylated or active form of ghrelin’s levels are examined, their fall after a meal is in proportion to the surgical and non-obese groups.[9,10] Additionally, variations in plasma ghrelin are seen with diurnal variations making comparison of studies all the more difficult.[31,32] In patients who go on a diet, ghrelin levels will rise. Following the gastric bypass operation, ghrelin levels will not rise as much, suggesting a period of satiety. The ghrelin levels appear to be dynamic and are more likely associated with total energy balance than satiety.[30] It is not clear how long they remain down, but it probably lasts for up to 15 months. This is interesting because those patients who undergo gastric bypass typically will see resumption of some degree of hunger between nine months and one year.

Figure 3

The glucagon-like peptides (GLP) are important anorexigenic peptides. GLP1 levels rise following the gastric bypass operation as well as the biliopancreatic diversion (BPD), otherwise known as the Scopinaro procedure. The RYGB results in prompt delivery of food to the terminal ileum thereby enhancing satiety, slowing motility, and increasing GLP-1 release. These effects may act synergistically to enable the effective weight loss seen with the RYGB. The levels do not increase after the vertical banded gastroplasty. GLP1 has certain important functions within the body, which include reduced gastric emptying, increased insulin sensitivity, reduced hepatic gluconeogenesis, and reduced pancreatic glucagon secretion. Levels increase and remain elevated for 20 years following these procedures.[12,13] GLP-1 levels differentially increase postoperatively in non-diabetics, compared to diabetics.[28] This differential incretin stimulation may account for the phenomenon of hyperinsulemic hypoglycemia seen postoperatively in some non-diabetic patients.

GLP1 analogues have been useful in the treatment of type 2 diabetes and are currently being tested in ongoing clinical studies. The effects of GLP1 administration can be overcome by administration of ghrelin.[14] There are many other types of peptides that may be useful for the treatment of obesity. Peptide Y for example may be is administered intranasally that may have central action at the neuropeptide Y receptors in the arcuate nucleus to inhibit appetite.[15] The interplay of the incretins, predominantly GIP and GLP-1 are responsible for approximately 50 percent of postprandial insulin.1 GLP-1 is secreted after meals from the L-cells of the distal small intestine and proximal colon and is thought to enhance insulin secretion in response to glucose through actions on the pancreas.

Additionally, GLP-1 induces satiety. In previous studies, the levels of GLP-1 have been found to transiently increase 180 minutes after BPD.[2] In 1987, Kreymann found that GLP-1 increased insulin secretion following a glucose load and caused a reciprocal decrease in serum glucose and glucagon levels.[3] From these data, GLP-1 was theorized to play a role in the physiology of dumping syndrome. Non-significant changes have been seen at delayed times from surgery in patients undergoing RYGB or jejuno-ileal bypasses.[4-6]
The combination of RYGB and GLP-1 has been speculated to be a contributor to weight loss after surgery and resolution of insulin resistance. After RYGB, not only is weight loss attributed to restriction and malabsorption, but it also has been theorized that the more rapid transit time of food into the ileum enhances peptide YY and GLP-1 release with a more rapid insulin response postprandially.[1,7]

GIP is secreted by the duodenal K-cells and has the effect of inhibiting intestinal motility and assists in the modulation of insulin secretion after a glucose load. Our data suggest that there are minimal effects of surgical status on GIP levels. This has been noted by Rubino and colleagues as well.[5] In patients with T2DM, there is a defect for GIP on the b cell receptor of the pancreas. This may make any subsequent postprandial changes following the gastric bypass of less significance.[8,9] NPY stimulates the desire to eat. We were able to show non-significant decreases postoperatively in both diabetics and non-diabetics. Again, Rubino and colleagues have demonstrated similar non-significant decreases in NPY levels. The postoperative levels of insulin have been reported to be significantly as well as non-significantly reduced after surgery.[5,6,10,11] Our data suggest that there was essentially no difference in levels preoperatively compared to postoperatively in diabetics and non-diabetics. Some of this data are made more confusing for those patients who are postprandial. The multiple stimuli for insulin secretion and the diabetic and operative status of the patients make these data difficult to interpret.

Another product of the intestinal L cells is PYY. (An outstanding review of this topic was recently published by Ballantyne, et al. in Obesity Surgery.[34]) It is found in its greatest concentrations in the terminal ileum and in the colon. Its secretion is stimulated by numerous factors such as cholecystokinin and vasoactive intestinal peptide (VIP). PYY is acted upon by the dipeptidyl peptidase enzyme IV (DPP-IV), which also breaks down GLP-1. Incidentally DPP-IV inhibitors are an important class of medications used in the treatment of type 2 diabetes. Unlike GLP-1 mimetics these medications can be administered orally. There are two active forms that are produced which can cross the blood brain barrier. PYY (1-36) acts centrally at the ventromedial hypothalamus to stimulate appetite and to decrease metabolism. PYY (3-36) has the opposite effect. In the gut PYY decreases gastrointestinal motility as well a pancreatic exocrine and endocrine secretion. Generally speaking, PYY levels are depressed in obese patients in comparison to their lean counterparts. A discrete linear relationship has not been shown. Response to a mixed meal is blunted in obese patients in that they require more calories to elicit a similar response to lean subjects. Small bowel resections produce an increase in the level of PYY in many cases. PYY levels appear to increase somewhat following restrictive surgery. Following the gastric bypass basal levels remain low but there is an increase in the stimulated response in comparison to obese controls. Implications for the bariatric surgical population are unclear. Since DDP-IV levels seem to remain high following the BPD, there may be increased production of the anorexigenic form of PYY.


Body metabolism is an important aspect of the regulation of body weight. Body metabolism is a complex relationship of the energy necessary to perform life-sustaining functions, adaptive thermogenesis, the thermic effect of food, and activity. It has been postulated that obese patients have a slower metabolism than those patients who are not morbidly obese. However, when adjustments are made for fat-free mass, it appears that the metabolism of morbidly obese people is in fact equal to that of those who are not morbidly obese or are of normal weight.

Interesting observations have occurred in those patients who are perhaps on the way to becoming morbidly obese. A role has been postulated for those patients who are hypometabolic at one stage of their life, and as they gain weight, their metabolism comes to rest in a normal phase for their body weight in comparison to thin patients. In addition, some evidence exists that with weight loss there is a slowing of metabolism, which can be reversed by weight gain and the presence of excessive weight in weight-stable patients.[19–23]

A 1995 study by Lible, et al.,[24] in the New England Journal of Medicine reported that when patients lose 10 percent of their weight, their body temperatures and energy expenditure drop and this reduction is below what is predicted for these patients. However, when patients begin to gain weight above 10 percent of their resting weight (stable weight), body temperature will rise and energy expenditure will increase to a non-energy conservation mode. This is interesting, considering that energy production is tightly coupled to adenosine triphosphate (ATP) production; in patients who have gained weight, there appears to be an uncoupling of the energy production and electron transfer gradient, which is likely due to the action of uncoupling proteins.[21]

The majority of this evidence points to the presence of a fat mass set point that is tightly regulated and genetically predetermined, although more research is needed to fully explore this area. Following gastric bypass-associated massive weight loss, there does not appear to be the expected slowing of metabolism out of proportion to the change in fat-free mass.


Genetics most likely play a role in morbid obesity. As mentioned earlier, there are several causes for monogenic obesity. These include defects in the leptin receptor, defects in the leptin protein, and transcription of the melanocortin gene or the melanocortin receptor. There are also defects in sim1 gene production, which codes for the supraoptic nuclei. There are over 250 genetic abnormalities that support a polygenic cause of obesity, which probably form the bulk of most obesity cases.[6]


Morbid obesity is a complex disease. We have only begun to scratch the surface of the complex interplay between the brain, the gut, and the adipocyte. It appears that energy mechanics and metabolism form a tightly coupled process, with evidence suggesting some degree of predetermination. Why there is a rapid increase in morbid obesity remains a question to be answered, but it may be related to the fact that obesity represents an important survival instinct. Three hundred thousand years ago, those humans who did not have the capacity to adequately store food in the form of fat during prolonged periods of starvation would not be candidates for survival. At that time, that was the gene that made humans the most fit.

Today, nothing could be further from the truth, as people who can consume significant amounts of food yet not store food in the form of fat appear to have a better survival rate. Gastric bypass and other obesity procedures, either purely restrictive or malabsorptive, are good models for the study of the treatment of morbid obesity. The massive sustained weight loss from these operations gives us insight into the metabolic and physiologic changes that accompany massive weight loss.


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Category: Metabolic Perspective

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