Metabolic Integration 2:Energy balance, the “diabesity” epidemic,

biochemistry of nutrition and exerciseBioc 460 Spring 2008 - Lecture 41 (Miesfeld)

Leptin is released from visceral fat and

controls neuronal signaling in the brain

James Neel, M.D., proposed the term “thrifty gene” to

explain the role of genes and lifestyle in “diabesity”

Metformin

Metformin

• Energy balance refers to the metabolic state in which the Calories contained in the metabolic fuel you consume are equal to the Calories you expend as a result of chemical reactions in the body, muscle contraction, and thermogenesis.

• Leptin is a peptide hormone that is secreted by visceral adipose tissue in proportion to the amount of stored lipid. Since leptin inhibits appetite and increases energy expenditure, it may represent a molecular “fat-o-stat.”

• Choosing oils that low in saturated fats, and carbohydrates with a low glycemic index, can add value to your food. Metabolic regulation and signal transduction through AMPK and PPAR appear to be key components of this mechanism.

• Studies have suggested that regular moderate to intense physical exercise can stimulate signaling pathways in muscle cells that reduce the risks of cardiovascular disease even if this regimen does result in significant weight loss.

Key Concepts in Metabolic Integration

The “Diabesity” Epidemic

Almost two-thirds of adults in the United States are either overweight (BMI of 25-30) or obese (BMI >30), and nearly one-third of children ages 6-18 fit these same descriptions. Moreover, the incidence of type 2 diabetes in children has increased ten-fold in the last 15 years.

Metabolic Energy Balance

The concept of energy balance can be used to explain how energy input (food calories) and energy expenditure (basal metabolism, physical activity, exercise) alter metabolic homeostasis to bring about a measurable weight gain or weight loss as reflected in the amount of stored fat in the body. By consuming an extra ~115 calories/day for a month (total of ~3500 calories), you will add one pound of stored fat to your body.

The Thrifty Gene Hypothesis

James Neel, a University of Michigan physician scientist proposed his thrifty gene hypothesis to explain the genetic basis for obesity and diabetes. Neel proposed that humans contain gene variants (thrifty genes) that favor individuals with a capacity to store extra fat during times of feast as a way to prolong survival during times of famine.

Pima Indians of southern Arizona have rates of obesity and type 2 diabetes that are among the highest in the world. However, a second population of Pima Indians in northern Mexico that are genetically similar and speak the same language, weigh on average 57 pounds less than their Arizona relatives and the incidence of diabetes is almost nine times lower.

The Thrifty Gene Hypothesis

Neel argued that while this genetic background was a good thing to have when humans depended on a hunter and gatherer lifestyle, these same thrifty gene variants become disease genes in a modern society where high fat foods and sedentary lifestyles are common.

While it is still not clear what the most likely candidates are for these thrifty genes, key suspects include signaling proteins that control metabolic homeostasis and genes encoding glucose and lipid metabolizing enzymes.

Leptin Controls Appetite and Energy Expenditure

A major breakthrough in obesity research came in 1994 when Jeffery Friedman and his colleagues at Rockefeller University identified a gene mutation in a strain of obese mice called OB (obese). The mutant gene was named leptin after the Greek word leptos which means thin.

Friedman's lab demonstrated that the molecular defect in a second strain of obese mice called DB (diabetic), was in fact due to a mutation in the leptin receptor. The phenotypes of OB and DB mice are very similar in that both are grossly overweight and have elevated levels of glucose and insulin in the serum due to insulin-resistance.

Leptin may be a type of“fat-o-stat”

Following a period of positive energy balance, fat stores increase, which results in elevated serum levels of leptin and subsequent activation of neuronal signals that decrease appetite and increase energy expenditure. This returns the body to its normal set point weight.

Leptin may be a type of “fat-o-stat”

Leptin receptor activation in the hypothalamus controls appetite and energy expenditure through a complex hierarchical neuronal signaling scheme that involves first order and second order neurons.

Basically, leptin activates neurons in the brain that relay the message to stop eating and start exercising, while at the same time, inhibiting neurons that normally relay the message to eat more and exercise less. Insulin has a similar effect on these same neurons.

Two peptide hormones synthesized in the stomach (ghrelin), and small intestine (PYY3-36), also control appetite and energy

expenditure. Ghrelin signals hunger when there is no food in the intestine, whereas, PYY3-36 signals full when food is in the intestine.

Based on the function and localized secretion of ghrelin and PYY3-36, why is it good advice to eat slowly if you are trying to lose weight?

Why does it make sense that leptin and insulin have the same effect on neuronal signaling, what signal are they each sending to the brain?

Metabolic link between obesity and type 2 diabetes

Insulin-resistant type 2 diabetes is distinct from type 1 diabetes in that type 1 diabetes is due to insufficient insulin production by the pancreatic cells, whereas, type 2 diabetes is characterized by desensitization of insulin receptor signaling.

As shown by a glucose tolerance test, both type 1 and type 2 diabetes are associated with elevated serum glucose levels and abnormal glucose clearance kinetics, however, only type 1 diabetes has a normal response to insulin treatment.

Metabolic link between obesity and diabetes

Research over that past twenty years have implicated that both genes and environment contribute to the development of obesity and type 2 diabetes.

In many cases, obesity leads to prediabetic symptoms that are characterized by elevated levels of serum glucose (hyperglycemia) and over-production of insulin (insulinaemia). If this condition persists, it will lead to insulin-resistance, and eventually, clinical type 2 diabetes.

Note that type 2 diabetes can also be initiated independent of obesity as a consequence of genetic defects that alter insulin signaling pathways.

Metabolic link between obesity and diabetes

Four classes of drugs have been developed to treat type 2 diabetes:

1) Migitol inhibits the intestinal -glucosidase to reduce carbohydrate uptake in the small intestine.

2) Glipizide is a sulfonylurea drug that inhibits pancreatic ATP-dependent K+ channel and thereby stimulates insulin release.

3) Metfomin is an activator of AMP-activated kinase (AMPK)

4) Thiazolidinediones (TZDs) are PPAR agonist that activate lipid metabolism in adipocytes and increase insulin sensitivity.

Treatment of Type 2 Diabetes

Treatment of Type 2 Diabetes

Biochemistry of Nutrition and Exercise

The three primary factors influencing metabolic homeostasis are genetic

inheritance, nutrition, and exercise.

Maintaining a healthy weight significantly lowers the risk of type 2

diabetes and cardiovascular disease, and moreover, recent studies have

suggested that some types of cancers may also be linked to obesity.

Although there is no escaping the biochemical reality that energy balance

determines body weight, not all foods of equal calories provide the same

nutritional value, and therefore what you eat, can be almost as

important as how much you eat.

Strategies to Lose Weight

One of the oldest drugs used to induce weight loss is ephedrine which

acts indirectly to stimulate adrenergic receptor signaling through

enhanced release of noradrenaline, a catecholamine signaling molecule.

The pancreatic lipase inhibitor orlistat, which goes by the

pharmaceutical name Xenical, can be taken in pill form before a meal to

limit fat absorption. By inhibiting the hydrolytic action of pancreatic lipase

in the small intestine, dietary triglycerides pass through the

gastrointestinal tract and are excreted.

A complementary strategy is to replace fats in processed foods with a fat

substitute such as olestra that cannot be digested. Olestra is a sucrose

molecule that has been chemically modified to contain up to eight fatty

acyl groups.

Strategies to Lose Weight

Most Diets Work About the Same in the End

Forty participants started on each diet, but 14-20 people dropped out. How might this affect the data analysis in terms of effectiveness?

Good Calories and Bad Calories

Good Calories and Bad Calories

The glycemic index (GI) is a numerical value that indicates how quickly

glucose is released into the blood after eating different types of

carbohydrate-containing foods. Low GI is better for you because it

prevents a spike in insulin levels which would lead to fat synthesis.

Biochemistry of Nutrition and Exercise

Achieving energy balance requires that both Caloric intake and Caloric

expenditure be equal. Considering that an average person burns about

70 Calories/hour when at rest (1700 Calories/day), one would need to

expend another 300 Calories/day through physical activity to maintain

energy balance on a 2000 Calorie/day diet.

This could be done by combining a number of passive activities such as

walking briskly to work (170 Calories), taking the stairs instead of the

elevator (240 Calories), or even vacuuming (130 Calories).

In ancient times, the energy expenditure required to obtain food was

sufficient to maintain energy balance, and therefore, high levels of

physical activity was a part of daily life.

Biochemistry of Nutrition and Exercise

Exercise is Beneficial Even Without Weight Loss

Group 1 did not exercise at all, group 2 performed exercise three times a

week at moderate intensity, and group 3 performed the same exercise

regimen but at high intensity. Group 3 had the biggest metabolic benefit.

One of the most important mechanisms to provide a steady supply of ATP for muscle contraction is exercised-induced activation of AMPK signaling.

AMPK alters metabolic flux through energy converting pathways to increase ATP production. AMPK is a heterotrimeric protein that is highly conserved in eukaryotes and consists of a catalytic subunit, a regulatory subunit that binds AMP, and the subunit which functions as a molecular scaffold.

Exercise-induced increases in the [AMP]/[ATP] ratio (low energy charge) leads to AMP binding to the subunit. This leads to a conformational change in the complex that facilities phosphorylation of a threonine residue (Thr172) in the catalytic domain of the subunit.

Numerous AMPK target proteins have been identified in skeletal muscle cells.

AMPK Signaling is Activated by Exercise

AMPK Signaling is Activated by Exercise

What mechanisms would reduce AMPK activity when exercise is over and the ATP levels in the muscle return to normal?