01. Gene therapy Boulikas.pdf - Gene therapy & Molecular Biology

XLI. Gene therapy for obesity
A. Molecular mechanisms of obesity
Obesity results from an imbalance in the mechanisms
which control storage of energy as triglycerides in adipose
cells versus energy expenditure. The identification of the
ob gene, and its encoded protein leptin, as subfunctional in
obesity (Zhang et al, 1994) has advanced our
understanding on the mechanisms of receival and
integration of a feedback signaling reflecting the amount
of adipose energy stores (reviewed by Spiegelman and
Flier, 1996). Further advancement was the identification
of the db gene (also known as OB-R gene) on mouse
chromosome 4 encoding the receptor of leptin which is
expressed primarily in the hypothalamus and choroid
plexus; OB-R is a single membrane-spanning receptor
most related to the gp130 signal-transducing component of
the IL-6 receptor, the G-CSF receptor, and the LIF
receptor (Tartaglia et al, 1995).
The leptin is a hormone which is secreted from the
white adipose tissue as a plasma protein, that acts in the
hypothalamus to regulate the size of the body fat depot;
the leptin with its receptor constitute a hormone-receptor
pair that signals the status and magnitude of energy (fat)
stores to the brain serving as an adipostatic signal to
reduce food intake and body weight. Leptin might have
evolved to inform the brain that energy stores in adipose
tissue are sufficient but also to trigger a neuroendocrine
response to fasting and limitation of food intake (Ahima et
al, 1996). Leptin also acts acutely to increase glucose
metabolism after intravenous and intracerebroventricular
administrations; both intravenous or
intracerebroventricular infusion of leptin into wild-type
mice increased glucose turnover and glucose uptake (the
plasma levels of insulin and glucose did not change), but
decreased hepatic glycogen content; thus, the effects of
leptin on glucose metabolism are mediated by the central
nervous system (Kamohara et al, 1997).
Plasma leptin was found to be highly correlated with
body mass index (BMI) in rodents and in 87 lean and
obese humans. In humans, there was variability in plasma
leptin at each BMI group suggesting that there are
differences in its secretion rate from fat. Weight loss due
to food restriction was associated with a decrease in
plasma leptin in samples from mice and obese humans
(Maffei et al, 1995).
B. Animal models for obesity
A number of rodent models for obesity are being used
in the laboratories including db/db, fa/fa, yellow (Ay/a)
VMH-lesioned, and those induced by gold thioglucose,
monosodium glutamate, and by transgenic ablation of
brown adipose tissue. The ob/ob mouse is genetically
deficient in leptin. The expression of leptin mRNA and the
Boulikas: An overview on gene therapy
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level of circulating leptin are increased in these animal
models, suggesting resistance to one or more of the actions
of leptin. High-fat diet was found to evoke a sustained
increase in circulating leptin in normal FVB mice and
FVB mice with transgene-induced ablation of brown
adipose tissue; leptin levels were found to accurately
reflect the amount of body lipid across a broad range of
body fat. However, despite increased leptin levels, animals
fed a high-fat diet became obese without decreasing their
caloric intake, suggesting that a high content of dietary fat
limits the action of leptin (Frederich et al, 1995).
Peripheral and central administration of microgram doses
of OB (leptin) protein reduced food intake and body
weight of ob/ob and diet-induced obese mice but not in
db/db obese mice (Campfield et al, 1995).
Body weight and adiposity appear to play a critical
role in the timing of puberty in humans and rodents.
Leptin is the signal that informs the brain that energy
stores are sufficient to support the high energy demands of
reproduction, and may be a major determinant of the
timing of puberty. Indeed, injections of recombinant leptin
(once daily) in female mice showed an earlier onset of
three classic pubertal parameters (i.e., vaginal opening,
estrus, and cycling) compared with saline-injected
controls. In addition to its effects on body weight, chronic
leptin treatment restored puberty and fertility to ob/ob
mice with total leptin deficiency, and acute treatment with
leptin substantially corrected hypogonadism in mice
starved for 2 days without affecting body weight (Ahima
et al, 1997). In a different study leptin was found to play a
significant role in sustaining the male mouse reproductive
pathways: all leptin-treated ob/ob males fertilized normal
females mice that carried out normal pregnancies and
deliveries, demonstrating that the reproductive capacity of
sterile ob/ob males was corrected only with leptin
treatment (Mounzih et al, 1997).
C. Glucocorticoids and obesity
The crucial role of glucocorticoids in obesity and
insulin resistance and the actions of the OB protein leptin
on the hypothalamic-pituitary-adrenal axis suggest that
there is an important interaction of leptin with the
glucocorticoid system. Leptin inhibits cortisol production
in adrenocortical cells and therefore appears to be a
metabolic signal that directly acts on the adrenal gland
(Bornstein et al, 1997). Glucocorticoids play a key
inhibitory role in the action of leptin: the permissive role
of glucocorticoids in the establishment and maintenance of
obesity syndromes in rodents arises from that
glucocorticoids restrain the effect of leptin. Leptin injected
intracerebroventricularly in normal rats induced modest
reductions in body weight and food intake. In marked
contrast, the same dose of leptin had very potent and longlasting
effects in decreasing both body weight and food