Françoise J. Smith

The recent positional cloning of the mouse ob gene and its human homology has provided the basis to investigate the potential role of the ob gene product in body weight regulation. A biologically active form of recombinant mouse OB protein was overexpressed and purified to near homogeneity from a bacterial expression system. Peripheral and central administration of microgram doses of OB protein reduced food intake and body weight of ob/ob and diet-induced obese mice but not in db/db obese mice. The behavioral effects after brain administration suggest that OB protein can act directly on neuronal networks that control feeding and energy balance.

To assess the biological activity and tolerability of pegylated recombinant native human leptin (PEG-OB), 30 obese men (mean body mass index, 33.9 kg/m2) were randomized to a double-blind treatment with weekly sc injections of 20 mg PEG-OB or placebo for 12 weeks, in addition to a hypocaloric diet (deficit, 2 MJ/day). Body composition, energy expenditure, and metabolic parameters were measured before and after treatment. PEG-OB was generally well tolerated based on adverse event reports, lab values, and vital signs. Weekly sc PEG-OB led to sustained serum concentrations of PEG-OB and leptin throughout treatment. No significant differences in the delta or percent weight loss, percent body fat, sleeping metabolic rate, or respiratory quotient were observed between the PEG-OB and placebo groups. Percent change in serum triglycerides from baseline was significantly correlated with body weight loss in the PEG-OB group, but not in the placebo group. Although larger reductions in serum triglycerides were observed in the PEG-OB group compared with the placebo group, these differences were not statistically significant. We concluded that weekly injection of PEG-OB leads to sustained serum concentration of PEG-OB and leptin throughout the 12-week treatment period and is generally well tolerated. The trends observed in serum triglycerides suggest that a weekly 20-mg sc treatment with PEG-OB may have biological effects in obese men.

Leptin (ob protein) and glucagon-like peptide-1-(7-36) amide (GLP-1) are peptides recently proposed to be involved in the regulation of food intake. Although the ability of exogenous leptin and GLP-1 to modulate consummatory behavior is consistent with the suggestion that these peptides are endogenous regulatory agents, central administration of these peptides may have aversive side effects, which could explain the anorexia. In the present experiment, exposure to a saccharine taste was immediately followed by central administration of leptin or GLP-1 to determine if these drugs could produce a conditioned taste aversion (CTA) in rats. At doses equated for producing comparable reductions in short-term food intake, GLP-1, but not leptin, generated a robust CTA. Although leptin caused no aversion, this peptide was the only drug to cause relatively long-term reductions in food consumption (16 h) and body weight (24 h). Hence, the results indicate that central GLP-1 produces aversive side effects, and it is argued that these nonspecific effects may explain the anorectic actions of GLP-1.

We attempted to determine if euthyroid Graves's ophthalmopathy is a single entity or a heterogeneous group of disorders. Activity of long acting thyroid stimulator protector occurred in 31 of 33 patients with Graves's hyperthyroidism but in only nine of 17 with euthyroid Graves's ophthalmopathy. Of the euthyroid patients, six had protector activity and thyroid non-suppressibility; firm goiters and high titers of thyroid antibodies were the rule in this group. We believe that these patients have three autoimmune diseases: Hashimoto's thyroiditis, Graves's thyroid disease and Graves's ophthalmopathy. Five euthyroid patients had no detectable protector activity or thyroid antibodies and had normal thyroid suppressibility; the thyroid was generally normal in size and consistence. These patients are interpreted as having "isolated" Graves's ophthalmopathy without any autoimmune thyroid disease. The remaining six patients showed dissociation between protector activity and thyroid non-suppressibility and cannot be classified as yet. Euthyroidism in Graves's ophthalmopathy may have more than one cause.