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If a fat-free mouse is just what you need to weigh the impact of lipid biology on Alzheimer disease (AD) or other neurodegenerative diseases, then look no further than last Sunday’s Nature Medicine. Philipp Scherer and colleagues at the Albert Einstein University in New York, and the University of Alabama at Birmingham, describe a novel way to turn on, and off, apoptosis in adipocytes.

Lipid biology is closely related to AD. ApoE4 (see ARF related news story), cholesterol, and obesity (see ARF related news story), for example, are all risk factors for the disease, while leptin, the satiety hormone released by adipose tissue, may attenuate production of amyloid-β (see ARF related news story). So, the new mouse model could prove useful for teasing out the complex relationships among fat cells, plasma lipids, and the brain.

To develop the fatless mouse, nicknamed FAT-ATTAC (for fat apoptosis through targeted activation of caspase 8), joint lead authors Utpal Pajvani and Maria Trujillo and their colleagues engineered an adipocyte-specific chimera comprising caspase 8 and a variant of the FK506 binding protein called FKBPv. FKBPv binds with extremely high affinity to FK1012 (two FK506s); hence, in the presence of FK1012, or its tighter-binding cousin AP20187, the chimera dimerizes, activates caspase 8, and sets off apoptosis, or programmed cell death. By coupling this chimera to the fat cell-specific Fabp4 promoter, the authors ensured that other cells would not be damaged by administration of the dimerizer.

image

Adipocytes can be FAT-ATTACked
Adipocytes exposed to dimerizer (right) shrink within 36 hours, while mock-treated cells remain as big as ever. [Image courtesy Nature Medicine and Philipp Scherer. First published in Nat Med. 2005 Jun 19; (Epub ahead of print).]

Pajvani, Trujillo and colleagues found that 7 days' worth of AP20187 was sufficient to disrupt adipose tissue in FAT-ATTAC transgenic mice, while longer (2- to 3-week) treatment led to rampant apoptosis in both white and brown adipose tissue. Despite the loss of these tissues, fat levels in the liver remained normal, as did circulating insulin, glucose, and triglycerides. Not unexpectedly, the adipose secretary proteins adiponectin and resistin were dramatically reduced in the plasma—by over 95 percent within 7 days of AP20187 treatment—as was serum leptin, the satiety hormone.

One of the remarkable aspects of this mouse is that the lipoatrophy can be reversed, although with mixed results. Six weeks after removal of the dimerizer, Pajvani, Trujillo and colleagues found that the FAT-ATTAC mice were returning to a more normal state, becoming heavier and laying down body fat. But the animals were glucose-intolerant, a condition the authors attributed to poor circulating adiponectin, which is thought to increase sensitivity to insulin. In mice that had been weaned off the dimerizer for six weeks, adiponectin levels returned to only about 50 percent of pre-treatment levels. Leptin levels were also reduced, and the animals had about a 50 percent increase in food intake.

Philipp Scherer, the principal author on the paper, expects that the FAT-ATTAC mice will be extremely useful for studying a wide range of lipid biology, including, but not limited to, the crosstalk between adipose tissue and the pancreas, the role of adipose tissue in inflammation, and the impact of adipose-derived signaling factors on food intake and energy expenditure.

In fact, his lab has already begun to study several of these relationships. By crossing FAT-ATTAC mice with ob/ob obese mice, which have no leptin, the authors have found that the relationship between the pancreas and the adipose tissue may be much more complicated than is generally appreciated. Ob/ob mice, for example, have elevated plasma insulin. But FAT-ATTAC ob/ob mice, which not only have no leptin, but no fat, have only about half the normal insulin. The fatless FAT-ATTAC ob/ob mice also failed a glucose-tolerance test, indicating that something is amiss with glucose-stimulated insulin secretion in these animals. What that might be is β3 adrenergic signaling. Activation of β3 adrenergic receptors normally stimulates insulin secretion, but as these receptors are adipocyte-specific in mice, they are absent from the fatless animals. This, plus other results, make the authors conclude “…that mere deletion of adipose tissue is not the simple solution to type 2 diabetes.”

The authors also found that adipose tissue may be important in inflammatory responses. When they challenged fatless FAT-ATTAC mice with the bacterial toxin lipopolysaccharide (LPS), they found that the mice had much lower levels of serum amyloid A3 and interleukin 6, two proinflammatory markers. In fact, basal levels of IL-6 were lower in fatless mice than in controls. “This work highlights the important contributions of the adipocyte towards systemic inflammation and underlines the intense local, paracrine crosstalk between the adipocyte and the macrophage,” said Scherer, who also noted that he does not want to exclude the possibility that this model may be used in the context of Alzheimer's research, as well. Of course, inflammation, particularly the role of macrophages, is another facet that has been linked to AD (see ARF related news story). —Tom Fagan.

Reference:
Pajvani UB, Trujillo ME, Combs TP, Iyengar P, Jelicks L, Roth KA, Kitsis RN, and Scherer PE. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy.

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  1. This mouse model seems to be a powerful tool to study different issues, the relationship between AD and lipids included. I am only surprised that cholesterol keeps being labelled as a risk factor for AD, despite the fact that in light of numerous old and particularly recent reports, this is completely unjustified. I would say that the concept about a positive relationship between AD and cholesterol should be announced as dead.

    References:

    . Does cholesterol act as a protector of cholinergic projections in Alzheimer's disease?. Lipids Health Dis. 2005;4:13. PubMed.

    . Is hypercholesterolemia a risk factor for Alzheimer's disease?. Mol Neurobiol. 2005;31(1-3):185-92. PubMed.

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