Integration ofMetabolism

Jack Blazyk3/4/04

Well-FedConditions

Only in America

Gly

coly

sis

Glycogenesis

PentoseShunt

Fatty AcidSynthesis

CholesterolSynthesis

TriglycerideSynthesis

Well-Fed Liver

Gly

coly

sis Pentose

Shunt

Fatty AcidSynthesis

CholesterolSynthesis

TriglycerideSynthesis

Well-Fed Adipose

Well-Fed Muscle

Glycogenesis

Insulin

RBC

Liver

Muscle

Adipose

Brain

Gut

Portal Vein

Lymphatics

Glucose

Glycogen

Glucose

CO2 + H2O

Protein

TG

Urea

Pancreas

Glucose

TG

Pyruvate

Lactate

Lactate

Chylomicrons

VLDL

Glycogen

CO2 + H2O

CO2 + H2O

Well-Fed State

FastingConditions

Fasting Liver

Glu

con

eog

enes

is

Fatty AcidOxidation

Ketone Body Synthesis

Glycogenolysis

Fasting Adipose

Fatty AcidOxidation

TriglycerideBreakdown

No Uptake

Fasting Muscle Fatty Acid

Oxidation

Ketone BodyUtilization

No Uptake

Glucagon

RBC

Liver

Muscle

Adipose

Brain

Gut

Portal Vein

Lymphatics

Glycogen

Glucose

Glu

cose

CO2 + H2O

Pancreas

Pyruvate

CO2 + H2O

Early Fasting State

CO2 + H2O

FA

FA

Lactate

Lactate

Glucagon

RBC

Liver

Muscle

Adipose

Brain

Gut

Portal Vein

Lymphatics

CO2 + H2O

Pancreas

Pyruvate CO2 + H2O

Extended Fasting State

KB

Lactate

FA

Glycerol

FA

CO2 + H2O

Protein

Cortisol

Glucose

Urea

Insulin

RBC

Liver

Muscle

Adipose

Brain

Gut

Portal Vein

Lymphatics

Glucose

Glycogen

Glucose

CO2 + H2O

Protein

TG

Urea

Pancreas

Glucose

TG

Pyruvate

Lactate

Lactate

Chylomicrons

VLDL

Glycogen

CO2 + H2O

CO2 + H2O

Well-Fed State

Glucagon

RBC

Liver

Muscle

Adipose

Brain

Gut

Portal Vein

Lymphatics

CO2 + H2O

Pancreas

Pyruvate CO2 + H2O

Extended Fasting State

KB

Lactate

FA

Glycerol

FA

CO2 + H2O

Protein

Cortisol

Glucose

Urea

http://arbl.cvmbs.colostate.edu/hbooks

Useful Endocrine & Metabolism Link

The magic mice of Salih Wakil

By Ruth SoRelle, MPH

In the midst of a pandemic of obesity and type 2 diabetes, Salih Wakil, PhD, chair of the Verna and Mars McLean Department of Biochemistry and Molecular Biology at Baylor College of Medicine, may have the answer to its control.

Certainly, the mice in his laboratory demonstrate that the veteran researcher and his colleagues at Baylor are on the right track. The work in Wakil’s laboratory centers around an enzyme called acetyl-CoA carboxylase (ACC) that exists in two forms – ACC1 and ACC2. When mice are genetically engineered so that they do not produce ACC2, the reaction sounds like something out of a snake-oil weight reduction advertisement. The mice can eat more and weigh less.

Salih Wakil, PhD

In fact, they can eat more of a high-fat, high-carbohydrate diet than mice that do produce the enzyme, and yet they do not gain as much weight nor do they develop type 2 diabetes.

The finding is just one in a long history of discoveries from Wakil’s lab that focuses on the synthesis and regulation of fatty acids. As he and his colleagues have unraveled the biochemical elements of how such fatty acids are formed and interact, they have come closer to a complete understanding of the secrets of fat metabolism.

In a recent paper in the Proceedings of the National Academy of Sciences, Wakil and his colleagues, Lutfi Abu-Elheiga, PhD, Wonkeun Oh, PhD, and Parichher Kordari reported on the mice that were genetically engineered to lack ACC2. For 22 weeks, these mice and normal counterparts ate a high-fat, high-carbohydrate diet. Yet the genetically engineered mice weighed less than the mice that produced ACC2 and were able to maintain normal insulin and glucose levels. The “normal” mice that made ACC2 developed a condition similar to type 2 diabetes and had high levels of both sugar and insulin in their blood.

A genetically engineered mouse, on the right, can eat more than his counterpart yet gain less weight.

ACC2’s role as a crucial element in the production of malonyl CoA is the secret to the svelte bodies and the health of the ACC2-deficient mice. Malonyl CoA inhibits the passage of fatty acid into the mitochondria, where it is burned to make energy. In the ACC2 deficient mouse, there is no mitochondrial malonyl-CoA, so the fatty acid passes the membrane into the mitochondria, where it is burned. This happens continuously.

“ACC2 is like running,” said Wakil. “When you run, you burn fat.”

“This implicates ACC2 as one of the targets in preventing diabetes by preventing the accumulation of fat in muscle cells, heart and liver,” said Abu-Elheiga, assistant professor of biochemistry at Baylor.

I ronically, ACC1 – the brother enzyme to ACC2 – is also key to the production of a pool of malonyl-CoA that resides elsewhere in the cell. “What’s interesting is that even though the mice continue to make malonyl-CoA, the two pools do not mix,” said Wakil. “One is in the cytoplasm and one is near the mitochondria.”

“I f we find a drug that inhibits this enzyme (ACC2), we can eat as much as we want without gaining weight. More importantly, we could protect people in their 40s and beyond who might become type 2 diabetics. People become fat, and fat is deposited in the muscle and liver, affecting glucose (sugar) transport from the outside into the cell. The amount of glucose from the blood going into the cell is reduced, and in the meantime, within the cell, you inhibit the insulin receptor. You increase the insulin levels and finally it doesn’t do any good. Blood sugar and insulin are both high. The person is a type 2 diabetic,” said Wakil.

Regulation

CarnitineShuttle

CoA-SH

CoA-SH

CH3-(CH2)14-C-S-CoA

O

=

Cytoplasm

Matrix

CH3-(CH2)14-C-S-CoA

O

=

Malonyl-CoA

X

I nflammatory Fat

Unraveling the injurious biology of obesity

Janet Raloff

The United States is big, and getting bigger each year—at least around its collective waistline. Federal statistics indicate that as of 2001, one in five U.S. adults was obese. That's roughly 45 million people. Almost twice that many fall into the next category, overweight. Some 15 percent of children, ordinarily the most active and trim segment of the population, are also too heavy. These figures are growing at a dizzying pace. For instance, the number of obese adults today is 74 percent higher than it was in 1991.

The problem isn't merely aesthetic. As people get fatter, they become more prone to a host of chronic diseases—including diabetes, atherosclerosis, and cancer—says a team at the Rand Corp. in Santa Monica, Calif., and other researchers.

In the January/February Health Affairs, the Rand group traces a dramatic share of disabilities in U.S. residents under 60 years of age to conditions fostered or aggravated by extra pounds. The team looked at back injury, other musculoskeletal problems, and diabetes. Experiencing the largest rise in obesity-related disabling injuries and illnesses are people aged 30 to 49 years, the team reports.

IS FAT WHERE IT'S AT? A new study links obesity and inflammation in these mice strains. The two animals are identical except for a mutation that renders the one at left excessively vulnerable to obesity and type 2 diabetes. Chen

Science News Online Week of Feb. 28, 2004; Vol. 165, No. 9

Two studies now offer a provocative clue. They've found that, with obesity, macrophages—cells in the body's immune army and not typically associated with fat—appear in abundance within fatty tissues. Moreover, macrophages seem to be a primary source of chemicals sparking inflammation in fat and beyond. It's possible that these immune troops have mistakenly read a call to arms and then run amok, bringing down allied cells instead of an enemy.

If the new macrophage-fat connection is confirmed, notes Gökhan S. Hotamisligil of the Harvard School of Public Health in Boston, researchers might succeed in decoupling obesity's link to chronic disease by aiming anti-inflammatory drugs at fatty tissue or the chemicals it spews.

Fat's companions

The body component that people call fat, scientists call adipose tissue. Adipocytes, the main cells making up that tissue, store fatty molecules derived from food. Interspersed with adipocytes is a mix of other cell types known collectively as stromal-vascular cells. These include endothelial, immune, and vascular smooth muscle cells. Normally, adipocytes vastly outnumber all their stromal-vascular neighbors.

As adipocytes increase in size, adipose tissue begins spewing inflammatory chemicals. One, for instance, is tumor necrosis factor-alpha, which can trigger insulin resistance. Which cells within adipose tissue secrete such chemicals had been ill-defined, Hotamisligil says, but "we were always a little biased that adipocytes were the source."

The two new reports now present evidence that the vast majority of inflammation-promoting agents comes from macrophages. Ordinarily, when the body senses disease or injury, it quickly converts some standby white blood cells into active duty as macrophages. Swooping into a damaged area from the bloodstream, macrophages gobble up cellular trash or infectious agents. Meanwhile, they secrete chemicals to rev up an even bigger immune attack by troops such as T cells and B cells.

In fat where there's no injury or infection, there wouldn't seem to be much of a role for macrophages. So, scientists studying obesity hadn't been on the alert for such cells. Moreover, because adipocytes can secrete inflammatory chemicals, scientists assumed they were behind virtually all inflammation associated with obesity.

Yet that's not what researchers recently found. Scientists at Millennium Pharmaceuticals in Cambridge, Mass., had been probing diabetes by studying what genes are turned on in a fat mouse that aren't active in a normal one. The expectation, notes geneticist Hong Chen, had been that obesity would switch on genes that alter the management of lipids or sugars.

"We thought we were working on a metabolic disease," she says, so the team paid special attention to enzymes that affect energy use and storage. The surprise, she told Science News, was that obesity generally turned on genes typically linked to inflammation. In fact, her team reports in the December 2003 Journal of Clinical Investigation, most of the obesity-activated genes have been associated specifically with macrophages.

Fat chance

Mounting evidence that inflammatory secretions from adipose tissue can foster disease has raised hope that these immune attacks might be treatable with anti-inflammatory drugs.

A little more than 2 years ago, Steven E. Shoelson of Harvard University's Joslin Diabetes Center in Boston and his colleagues reversed obesity-related insulin resistance in mice with high doses of aspirin. The anti-inflammatory drug worked by neutralizing IKK-beta, an inflammatory secretion associated with obesity, say the researchers.

Nine months later, a team led by Gerald I. Shulman of the Yale University School of Medicine treated nine obese diabetic people with high-dose aspirin for 2 weeks. The regimen temporarily improved the volunteers' responsiveness to insulin, leading to better control of their blood sugar. Indeed, the trial yielded blood sugar improvements comparable to those achieved with metformin, a common antidiabetes drug. The aspirin therapy also lowered fat concentrations circulating in volunteers' blood.

However, Shulman and his coauthors argued in the May 2002 Journal of Clinical Investigation that aspirin has too many side effects for long-term use against diabetes: "We would strongly advocate against its use for treatment of type 2 diabetes." Rather, the study's findings suggest new directions for drug development.

Such efforts might have to specifically target inflammatory molecules arising in adipose tissue, says Eckel. Macrophages offer infection-fighting benefits elsewhere in the body, so "you probably wouldn't want to shut down their activity systemically," he explains.

Better yet, Hotamisligil says, target new drugs at critical chemical processes that occur before macrophages multiply in fat and trigger the inflammation. Unfortunately, no one yet has a clue to what most of those upstream processes might be.