Not all body fat is created equal. Most of it is white and laysthe groundwork for obesity. The rest is brown and supposedlycurbs excess weight gain.
Brown adipose tissue (BAT) contains more mitochondria thanregular white fatty tissue and stores less energy. According toconventional wisdom, people with plenty of BAT burn off theirexcess calories before these ingested units of heat and energycan be stored as body fat.
Since the brown adipose tissue is widely dispersed and rapidlyrenewed, it is not possible to dissect all of the brown fat from amouse and observe this BAT-free state on body weight. Soinstead of using scalpels, Harvard researchers createdtransgenic mice who lack BAT and studied the rodents'behavior in balancing weight accretion and energy expenditure.The researchers' paper is in the current issue of Nature, titled"Development of obesity in transgenic mice after geneticablation of brown adipose tissue."
Endocrinologist Bradford Lowell of Boston's Beth Israel Hospitalis the paper's first author. His recorded telephone messageinforms the media PP for whom "obesity" is a hot button PP that"this tissue plays an important role in protecting mice againstthe development of obesity. The role of brown fat in humans ispresently unknown. At this time, we are not performing anystudies in humans concerning the role of brown fat."
The paper's principal author, Jeffrey Fliers, who is head ofendocrinology at Beth Israel, told BioWorld that further studiesnow aim "to understand the mechanism for the diabetes thatthe mouse develops and see if this model would be useful tostudy the relationship of obesity and diabetes on the one handand atherosclerosis on the other."
Flier summarized the little that's known about brown adiposetissue in humans. Babies seem to have reasonable amounts ofBAT, which diminishes with age, but "if you look with sensitivetechniques, you can find it in most humans, even when they'rerelatively older."
Flier said answers to BAT's role in human metabolism andweight profile are lacking because there is no "medically usefulmechanism for measuring the amount of BAT in a humanbody." A natural human experiment, he observed, ispheochromocytoma, a tumor of the adrenal gland's medulla,which involves a marked expansion of the amount of BAT, plusproduction of heat and loss of weight.
The molecular mechanism that Flier and his colleagues devisedto measure the effect of BAT in mice is based on the fact thatbrown adipose tissue contains more mitochondria than whitefat does. Indeed, mitochondria is what gives BAT its browncolor.
Because mitochondria, the cell's powerhouse, give off largequantities of excess heat, they also account for BAT's"inefficiency" in conserving the body's long-term energy stores.That job is "efficiently" handled by globules of white fat, whichwarehouse the energy in food calories.
Flier's BAT-excising scalpel was a toxic transgene, the DNAsequence-encoding diphtheria toxin's A chain fused to abrown-fat-specific promoter. The scientists microinjected thegenetic ablation vector into the pronuclei of fertilized mouseembryos.
Rodent progeny carrying this BAT-bombing trait put on weightas they grew, to the point of extreme obesity. As a result, fivetransgenic animals at 8 weeks of age had only one-eighth asmuch BAT as their control litter mates. They indulged inhyperphagia (overeating) and devoured 53 grams of food perweek; controls got by on 33 grams.
And these BAT-minus animals weighed 40 grams on average,compared with 25 for the normal BAT controls. What's more,nearly one-fourth of this body mass consisted of lipid, versus10 percent for the normals. By 19 weeks, pure fat accountedfor fully 50 percent of the low-BATs' body weight.
When the transgenic mice were exposed to environmental coldtheir core temperature dropped, providing additional evidenceof BAT dysfunction. This supports a finding by otherresearchers that brown fat mediates less than 40 percent of thethermogenic response to acute cold exposure, with shiveringtaking care of 60 percent, the Nature paper noted.
As their gross corpulence advanced, the transgenics developedseveral abnormalities associated with diabetes (hyperglycemia)and atherosclerosis (hypercholesterolaemia), which Flier'sgroup is now pursuing.
"This (BAT-lacking) transgenic mouse, by virtue of its normalfertility, linear growth and serum glucocorticoid levels,represents a valuable new model that may aid studies of thepathogenesis and treatment of human obesity and insulinresistance," Flier concluded.
In a Nature editorial, researcher Jeffrey Friedman ofRockefeller University suggested that the use of suchtransgenic mice, expressing toxin genes that can be turned onat different periods of development, might help confirm ordeny "the old notion that overeating or a decrease in activity inchildren may contribute to obesity later in life."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.