Which Comes First? The Obesity or the Insulin? The Behavior or the Biochemistry?
Article Outline
Abbreviations: IRKO, Insulin receptor knockout
Here's a curious paradox: if you give a 5-year-old child a cookie, what happens? He bounces off the walls. Referred to in the vernacular as the “sugar high,” this is actually the negative feedback system of energy balance at work. The cookie stimulates insulin release, which drives the calories into adipose tissue, which releases leptin, which circulates to reach the hypothalamus, which activates the sympathetic nervous system, which alters skeletal muscle mitochondrial energy efficiency to result in increased energy expenditure in the form of resting energy expenditure, voluntary energy expenditure, and finally non-exercise associated thermogenesis (also known as “fidgeting”)—all to maintain energy balance.1 But if you give an obese 5-year-old child a cookie, what happens? The child is in the pantry looking for more cookies. Clearly, this negative feedback system breaks down in obese people, and energy balance goes haywire.
See related article, p 612
The reason for this paradox can be described in 2 words: “leptin resistance.” Obesity is leptin resistance; after all, if an individual's leptin worked correctly, the individual would not be obese. However, when leptin cannot or does not signal the hypothalamus, the brain thinks it is starving. Sympathetic tone drops, leading to reduced energy expenditure and reduced quality of life, while vagal tone increases, leading to increased appetite and caloric intake—all perpetuating the obese state.2 Leptin levels fall within 12 hours of fasting; thus, an individual becomes leptin deficient (relative to the degree of resistance) even before body weight declines, accounting for the recidivism of obesity. When expressed this way, the phenomena of excess food intake, lack of exercise, and decreased quality of life of obese people are really the end result of a biochemical phenomenon. This revelation should not be novel to pediatricians, because diabetes insipidus, narcolepsy, and schizophrenia are other biochemical disorders that present as aberrant behaviors.
Although the etiology of leptin resistance remains unknown, its biochemical associations are legion. Insulin resistance and hyperinsulinemia are tightly linked with leptin resistance and obesity. The association is clear; however, the “holy grail” of obesity research is determining the directionality of the phenomenon (ie, which comes first?). In this issue of The Journal, Han et al3 describe the association between insulin resistance and calorie ingestion in obese children at a “metabolic buffet.” They show that the caloric intake during this voluntary unencumbered event correlates with HOMA (an index of insulin resistance), and the first phase of insulin secretion in response to the hyperglycemic bolus of their clamp. So, hyperinsulinemia, caused by either insulin resistance (eg, obese minority populations) or insulin hypersecretion (ie, children with hypothalamic obesity),4 appears to predict overeating. Controlling for numerous biochemical (eg, puberty) and demographic (eg, socioeconomic status) covariates did not alter this association. This concept is very important, because it both points to targeting insulin as a mode of obesity therapy (eg, metformin) and measuring fasting insulin, insulin resistance, or both in obese children to determine whether it signifies a comorbidity and whether it poses a barrier to obesity treatment. Currently, the American Academy of Pediatrics, the American Medical Association, and the American Diabetes Association do not support this approach. However, the Endocrine Society, in an upcoming clinical guideline, will consider the measurement of fasting insulin as an option in obese children.5
One major omission of Han et al is the lack of normal-weight control subjects, to determine the dynamic range of this relationship. Does the correlation between insulin and food intake exist only in obese people? Does being insulin sensitive mean anorexia? What about in adults? Do I have to stop frequenting the hotel breakfast buffet while at the Pediatric Academic Societies meeting? Food for thought
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The data of Han et al demonstrate that, in obese people, the more an individual eats, the more insulin resistant the individual is. Or is it the other way around? Unfortunately, this study does not establish directionality; no cross-sectional study can. However, the tight correlation between hyperinsulinemia and caloric intake gives us pause to view this association biochemically.
Which leads us to a second surviving paradox. Clearly, obesity is associated with insulin resistance. But if an individual is insulin resistant, shouldn't that prevent weight gain? After all, if cells are not responsive to insulin, then adipose tissue should not engage in lipogenesis to increase adiposity, and skeletal muscle should not engage in amino acid transport to increase muscle bulk. Indeed, some investigators have suggested that insulin resistance is actually a “defense mechanism” of obese people against further weight gain.
The answer to this paradox lies in the question, “Which tissue is insulin resistant?” If all tissues were equally and completely insulin resistant, you'd have leprechaunism or lipoatrophic diabetes or the Rabson-Mendenhall syndrome; these individuals would be just skin and bones, with intractable hyperglycemia and hyperinsulinemia, and they would die in short order. In obesity, the adipocyte must remain insulin sensitive at least up to a point. So, which tissues become insulin resistant to start the process? Ron Kahn's laboratory at Joslin demonstrated very nicely, with tissue-specific insulin receptor knockout (IRKO) mice, that differential tissue insulin resistance manifests as very different phenotypes.6 Of 8 different IRKO mice, which get fat? Only LIRKO (liver) and NIRKO (brain) mice get fat; the rest of the IRKO mice are thin, and the MIRKO (muscle) and FIRKO (white adipose tissue) mice are indeed protected against obesity. Similarly, when isolated hepatic insulin resistance is induced,7 the animal gets fat and hyperinsulinemic, and the other peripheral tissues become insulin resistant. However, when the hepatic insulin resistance is reversed,8 the animal slims down and the insulin resistance of all the other tissues improves as well.
Ever wonder why the pancreatic vein drains into the portal vein and not the vena cava? This is possible because the liver is the primary target of insulin action. There are 2 portal systems in the body: hypothalamus-pituitary (because the pituitary must be downstream of the hypothalamus to receive its signal) and pancreas-liver (because the liver must be downstream of the pancreas to receive its signal). So, which comes first—the insulin resistance or the obesity? If the problem starts in the liver, then the pancreas has to secrete more insulin by mass action to make the liver do its job; this raises insulin levels all over the body, promotes adipogenesis, and foments peripheral insulin resistance all at the same time. Alternatively, if the hypothalamus becomes insulin resistant first, the leptin signal is also antagonized there,2, 9 leading to increased appetite and weight gain and eventually peripheral insulin resistance. Unfortunately, measuring insulin resistance in humans in vivo, as Han et al3 did, does not show which tissues are insulin resistant at any given time. Instead, a “composite” insulin sensitivity is measured, which may not tell you which tissue(s) has the problem or where it started.
So, which comes first? It is not an academic exercise—identifying the initial lesion where obesity and insulin resistance begins has enormous implications for both prevention and treatment. But we do not have the technology or the longitudinal studies in humans to answer either question. Nevertheless, if our rodent models are any indication, we should recognize that it is a 2-way street. Behavior can alter biochemistry (eg, diet-induced obesity), but biochemistry can also alter behavior (eg, leptin resistance). Hepatic or central nervous system insulin resistance can come first, but we do not have the tools to recognize it; then comes the hyperinsulinemia, followed by the obesity, and finally the peripheral insulin resistance, in a vicious cycle. The moral is: when you see behavior, think biochemically.
References
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- Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat Med. 2004;10:268–274
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PII: S0022-3476(08)00062-0
doi:10.1016/j.jpeds.2008.01.021
© 2008 Mosby, Inc. All rights reserved.
Refers to article:
- Insulin Resistance, Hyperinsulinemia, and Energy Intake in Overweight Children , 07 March 2008
