Obesity and diabetes

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JCI Table Of Contents, March, 2006

11 Mar 2006

Fat rats reveal why short-term overeating can lead to obesity and

diabetes

Obesity is due to a mismatch between the number of calories we

consume and the amount of physical activity we undertake. In the

brain, a region called the hypothalamus control ours eating behavior

through its metabolism of fat molecules called fatty acids.

Interestingly, eating too much in the short-term can result in a

severe drop in the ability of the body (and brain) to be satisfied

by fat and to control blood sugar levels. In a study appearing

online on March 9 in advance of print publication in the April issue

of the Journal of Clinical Investigation, Luciano Rossetti and

colleagues at Albert Einstein College of Medicine in New York report

that inhibiting an enzyme in the liver called carnitine

palmitoyltransferase-1 (CPT1A), which is involved in metabolizing

fatty acids, inhibits feeding. The researchers placed normal rats on

a lard-based diet, which stimulated the animals to voluntarily

overeat and gain weight. When the researchers inhibited CPT1A by

delivering special molecules called " ribozymes " into the brain of

the rats, the animals ate dramatically less. The treatment also

improved the blood sugar levels of these animals, who suffered from

a common metabolic impairment known as insulin resistance, in which

the body is unable to respond properly to insulin. The authors

report that this animal model of diet-induced obesity and insulin

resistance displayed defective adaptation to an increase in fat

availability coupled with a severe impairment in the ability of the

brain to sense fat intake. Further studies will be required to

establish the critical role of this biochemical pathway in nutrient

sensing in other animal models and, critically, in humans.

TITLE: Restoration of hypothalamic lipid sensing normalizes energy

and glucose homeostasis in overfed rats

AUTHOR CONTACT: Luciano Rossetti

Albert Einstein College of Medicine, New York, New York, USA

Phone: ; Fax: ; E-mail:

rossetti@...

View the PDF of this article at: https://www.the-jci.org/article.php?

id=26640

CARDIOVASCULAR BIOLOGY

How sweet it is: scientists find cellular link between insulin

resistance and heart disease

Insulin resistance (IR) is a metabolic disorder in which the body

does not respond to the insulin produced by the pancreas, typically

resulting in elevated blood sugar levels and diabetes. Importantly,

individuals with diabetes also have a significantly higher risk of

developing cardiovascular disease (CVD), even after accounting for

risk factors such as elevated cholesterol levels and high blood

pressure. Now, in a study appearing online on March 9 in advance of

print publication in the April issue of the Journal of Clinical

Investigation, Brownlee and colleagues at Albert Einstein

College of Medicine in New York show a link between the metabolism

of lipids called free fatty acids (FFAs) and a tissue damaging

oxidant called " superoxide. " The researchers measured the effects of

FFA metabolism in cells from the aortas of cows, when the cells were

treated with a high sugar solution to mimic the events that occur in

the blood vessels during insulin resistance and diabetes. The

authors found that the cells metabolized FFAs, which led to

increased production of superoxide and the activation of a variety

of inflammatory signals previously implicated in high†" blood-

sugar†" induced vascular damage. In addition, the authors also found

that two important antiatherogenic enzymes, prostacyclin synthase

and eNOS, were inactivated, suggesting that insulin resistance and

high blood sugar can directly damage the cells of blood vessels,

contributing to heart disease. The researchers also examined mouse

and rat animal models of insulin resistance, and found that

inactivation of prostacyclin synthase and eNOS was prevented by

reduction of superoxide levels. The study results suggest that these

experiments have identified a novel mechanism that contributes to

the accelerated cardiovascular disease risk occurring in people with

insulin resistance.

TITLE: Insulin resistance reduces arterial prostacyclin synthase and

eNOS activities by increasing endothelial fatty acid oxidation

AUTHOR CONTACT: Brownlee

Albert Einstein College of Medicine, Bronx, New York, USA

Phone: ; Fax: ; E-mail:

brownlee@...

View the PDF of this article at: https://www.the-jci.org/article.php?

id=23354

ENDOCRINOLOGY

Creating vitamin D-related compounds with fewer side effects for the

treatment of osteoporosis and skin disorders

Vitamin D and drugs with structures similar to vitamin D, are called

vitamin D receptor (VDR) ligands because they exert their actions in

the body by binding to a special cell protein called the vitamin D

receptor. Importantly, VDR ligands are therapeutic agents for the

treatment of psoriasis, osteoporosis, and show immense therapeutic

potential for autoimmune diseases and cancers of skin, prostate,

colon, and breast as well as leukemia. However, the major side

effect of VDR ligands is hypercalcemia, which develops due to

adverse effects in the intestine. In a study appearing online on

March 9 in advance of print publication in the April issue of the

Journal of Clinical Investigation, researchers Sunil Nagpal and

colleagues at Eli Lilly and Company describe new drugs

called " tissue-selective VDR modulators " or VDRMs), which have high

activity in skin and bone, with poor activity in the intestine,

therefore reducing the negative side effects of these compounds. The

researcher designed two compounds called LY2108491 and LY2109866,

and found that mice treated with these compounds developed increased

thickness of the epidermal layer of their skin, a model which

suggests that the compounds will inhibit psoriasis-related symptoms

in humans. Using isolated human cells in laboratory dishes, the

authors also showed that these compounds have potent action in other

target cells such as keratinocytes of the skin, osteoblasts of bone,

and blood cells. Further work on these and related compounds may

lead to the development of potent treatments for cancers, psoriasis,

and osteoporosis that have fewer unwanted side effects.

TITLE: Identification and characterization of noncalcemic, tissue-

selective, nonsecosteroidal vitamin D receptor modulators

AUTHOR CONTACT: Sunil Nagpal

Eli Lilly and Company, Indianapolis, Indiana, USA

Phone: ; Fax: ; E-mail: nagpals@...

View the PDF of this article at: https://www.the-jci.org/article.php?

id=25901

NEPHROLOGY

Human gene mutation causes kidney stones and kidney failure

Mutations in a human gene known as Claudin16 are responsible for

certain causes of kidney failure and kidney stones, and increased

urine calcium and magnesium levels. However, the precise effects

that these different mutations have on claudin16 protein structure

and biological action are unclear. Now, in a study appearing online

on March 9 in advance of print publication in the April issue of the

Journal of Clinical Investigation, Walter Hunziker and colleagues

from the Institute of Molecular and Cell Biology in Singapore have

identified that the majority of mutations in claudin16, which is

normally located on the surface of kidney cells, cause the protein

to get stuck inside the cells or get degraded by the cell's own

protein-destroying machinery. The researchers created 21 synthetic

DNA molecules called " plasmids " which each contained a single mutant

form of the claudin16 gene sequence, and put these plasmids into

kidney cells in the laboratory. The cells were able to produce the

mutant claudin16 protein. The authors made an antibody that

recognized claudin16 protein and used it to determine where in the

cells the various mutants were localized. Incubating the cells with

this antibody revealed that most of the mutants, in contrast to the

normal version of claudin16, were either degraded by the cell or

they became trapped in various places inside the cell and thus could

not function properly. In addition, when the researchers examined

the movement of calcium and magnesium in and out of the cells, they

found that cells that expressed the mutant claudin16 forms of the

protein had defects in trafficking calcium and magnesium. The

authors report that this study is important for the potential future

therapeutic interventions that claudin16 corrective therapy may

provide for patients with excess calcium loss due to these genetic

mutations.

TITLE: Disease-associated mutations affect intracellular traffic and

paracellular Mg2+ transport function of Claudin-16

AUTHOR CONTACT: Walter Hunziker

Institute of Molecular and Cell Biology, Singapore

Phone: 65-6586-9599; Fax: 65-6779-1117; E-mail: hunziker@...-

star.edu.sg View the PDF of this article at: https://www.the-

jci.org/article.php?id=26323

IMMUNOLOGY

New mechanism for allergic asthma identified

In a study appearing online on March 9 in advance of print

publication in the April issue of the Journal of Clinical

Investigation, Gesine Hansen and colleagues at Medizinische

Hochschule Hannover in Germany have identified a potentially new

target for treating asthma. The researchers examined a mouse model

of asthma, which develops human-like asthma symptoms including

airway hyperresponsiveness (AHR), mucus production, production of

proinflammatory proteins called cytokines, and increased numbers of

immune cells called eosinophils and Th2 cells in the lung. The

researchers injected these asthmatic mice with an antibody that

stimulates the activity of an immune protein called CD137. A single

injection of this " agonistic " anti-CD137 antibody was able to

inhibit AHR, eosinophilic airway inflammation, and Th2 cytokine

production for the complete observation period of almost 7 weeks.

The lasting effects of this treatment suggest that this type of

antibody therapy may be used in the future to treat the recurring

symptoms of allergy in humans. Specifically, the authors suggest

that strategies aimed at stimulation of CD137, which has previously

been shown to induce tumor rejection, may represent a clinical

target for allergic inflammatory responses and other disorders

characterized by inappropriate T cell activation.