Metabolic Integration 2:

Energy balance, the “diabesity” epidemic, biochemistry of nutrition and exercise

Bioc 460 Spring 2008 - Lecture 41 (Miesfeld)

Metformin James Neel, M.D., proposed the term “thrifty gene” to explain the role of genes and lifestyle in “diabesity” Leptin is released from visceral fat and controls neuronal signaling in the brain

Metformin

Key Concepts

in Metabolic Integration

• 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.

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

leptos

after the Greek word 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 (

PYY 3-36

), also control appetite and energy expenditure.

Ghrelin signals hunger

when there is no food in the intestine, whereas,

PYY 3-36 signals full

when food is in the intestine.

Based on the function and localized secretion of ghrelin and PYY 3-36 , 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

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.

Treatment of Type 2 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

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

.

AMPK Signaling is Activated by Exercise

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

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