Cellular program controlling the recovery of adipose tissue mass: An in vivo imaging approach

Abstract

The cellular program responsible for the restoration of adipose tissue mass after weight loss is largely uncharacterized. Leptin mRNA levels are highly correlated with adipose tissue mass, and leptin expression can thus be used as a surrogate for changes in the amount of adipose tissue. To further study the responses of adipocytes to changes in weight, we created a transgenic mouse expressing the luciferase reporter gene under the control of leptin regulatory sequences, which allows noninvasive imaging of the leptin expression of mice in vivo. We used these animals to show that weight loss induced by fasting or leptin treatment results in the retention of lipid-depleted adipocytes in adipose depots. To further study the cellular response to weight regain after leptin treatment, a leptin withdrawal protocol was used to induce a state of acute leptin deficiency in wild type mice. Acute leptin deficiency led to the transient deposition of large amounts of glycogen within pre-existing, lipid-depleted adipocytes. This was followed by rapid reaccumulation of lipid. Transcriptional profiling revealed that this cellular response was associated with induction of mRNAs for the entire pathway of enzymes necessary to convert glucose into acetyl-CoA and glycerol, key substrates for the synthesis of triglycerides.adipocytes ͉ leptin ͉ luciferase

A comparative perspective on lipid storage in animals

“…Leptin is a major adipokine that is primarily produced by mature fat cells and whose expression is highly correlated with the degree of adiposity Birsoy et al, 2008b). Increase in fat mass in mammals causes an increase in the amount of leptin, which provides an afferent signal to the hypothalamus to decrease food intake and increase energy expenditure, thus keeping the body weight stable (Friedman and Halaas, 1998).…”

Noninvasive tracking of gene expression by reporter transgene imaging

“…In their report, Birsoy et al (2) employ this index of fat mass to show that fat loss by starvation or leptin treatment depletes triglycerides from adipocytes without impairing their viability or their ability to reaccumulate lipids. This confirms the demonstration by Hirsch's group (5) that adipocytes do not disappear during long-term semistarvation and, more recently, that leptin-induced lipid depletion does not destroy adipocytes but rather transforms them into mitochondria-rich, fat-burning cells (6) that can redifferentiate into normal adipocytes (7).…”

“…Ectopic lipid deposition can cause lipotoxic damage to important organs, and this has been proposed as an etiology of the metabolic syndrome and type 2 diabetes (9, 10); the technique of Birsoy et al (2) might permit the tracking of both leptin expression and expression of the leptin receptor, Lepr-b, in age-matched, diet-matched transgenic littermates. If so, one could test the hypothesis that prevention of the metabolic syndrome requires reciprocal down-regulation of adipocyte Lepr-b during overfeeding for storage of triglycerides in adipocytes (11), but full expression of Lepr-b in the peripheral targets to maintain leptin's lipooxidative actions in nonadipose tissue.…”

“…Until now, gene expression chronology has required tissue samples from groups of animals killed at multiple arbitrary time points. The technique of Birsoy et al (2) should permit continuous tracings of the expression level of genes of interest by means of reporter transgenes such as luciferase and, perhaps, other reporter proteins. Gene expression chronology may be very useful in attempting to define their functional role in various homeostatic responses to experimental perturbations or during the evolution of diseases in which random sampling of tissues reveals changes in gene expression and multiple pathologic events but fails to indicate their precise chronologic relationships.…”

“…I n this issue of PNAS, the laboratory that discovered leptin (1) reports the development of a novel in vivo imaging strategy that permits noninvasive estimation of leptin expression (2). They have engineered a BAC transgenic mouse strain expressing a luciferase reporter gene under the control of adipocyte-specific leptin regulatory sequences.…”