In the journal Cell, researchers report the serendipitous discovery that the initial development of fat requires a "remodeling" protein that must first make way for the lipid-laden tissue's growth. An enzyme that "chews" through collagen fibers sculpts the matrix surrounding fat cells, allowing them to expand and mature, the team reports.
In the absence of the collagen-busting "membrane-anchored metalloproteinase" (MT1-MMP), would-be fat cells, or preadipocytes, fail to break through the fibrous extracellular matrix, they found. Moreover, the cells entrapment within a dense collagen meshwork disrupts their structure. That structural change, in turn, stalls the genetic programs critical for full-blown fat development, leading to sweeping changes in gene activity.
In contrast, they report, fat cells deficient for MT1-MMP develop apparently normally when placed on the flat surface of a laboratory dish.
"When small fat cells embedded in what is essentially a 3D molecular cage receive the appropriate external signals during development, it appears that they change their geometry--remodeling the surrounding matrix using an enzyme to chew the fibers," said the study's senior author Stephen Weiss of the University of Michigan, Ann Arbor.
For reasons that are not entirely clear, that shape change leads to a dramatic shift in gene expression and cell behavior, he added. In the absence of the collagen-rich 3-dimensional matrix, the MT1-MMP enzyme apparently becomes irrelevant.
The study identifies MT1-MMP as a "heretofore unsuspected 3-dimensional matrix specific regulator of white adipose tissue development and function," the researchers said. White adipose tissue is a type of fat that serves as a primary depot for energy stores.
Moreover, the findings in developing mice raise the possibility that the enzyme might also play an important role in the remodeling of extracellular barriers in adult animals as they gain or burn fat, he said.
In the beginning, the study's lead author Tae-Hwa Chun, also of the University of Michigan, wasn't particularly interested in fat, Weiss noted. Rather, he had set out to examine the effects of MT1-MMP on blood vessels in mice deficient for the enzyme.
Chun soon noticed, however, that the mice seemed to have an unexpected lack of white adipose tissue. Indeed, they later confirmed that the only white fat the mice had consisted of abnormally small "mini-adipocytes."
Weiss first suspected the mutant mice were simply malnourished as a result of their other deficiencies. However, the seemingly normal quantities of heat-generating brown fat retained by the developing mice challenged that notion.
To get to the root of the problem, the team screened the activity of genes in the white fat cells of normal mice versus those deficient for MT1-MMP.
"That was our first really big surprise," Weiss said. "From the loss of a single enzyme, we expected focused changes in gene expression. Instead, we saw broad changes in many, many genes."
The finding raised a big question, he said: "Why would a little cutting enzyme have such a grand effect on seemingly unrelated genes?"
They next isolated undifferentiated preadipocytes from mice lacking the collagenase in an attempt to zero in on the defects. In the 2-dimensional environment of the laboratory dish, however, the fat precursors turned into mature fat cells "with no problem," leading the team to question whether the defect truly resided within the fat cells or was perhaps a result of deficiencies in neighboring cells, such as blood vessels or nerves, Weiss said.
When the researchers transplanted the mutant preadipocytes into otherwise normal mice, however, their defect again surfaced.