Inhibition of brain carnitine palmitoyl-transferase-1 (CPT-1) is reported to decrease food intake and body weight in rats. Yet, the fatty acid synthase (FAS) inhibitor and CPT-1 stimulator C75 produces hypophagia and weight loss when given to rodents intracerebroventricularly (icv). Thus roles and relative contributions of altered brain CPT-1 activity and fatty acid oxidation in these phenomena remain unclarified. We administered compounds that target FAS or CPT-1 to mice by single icv bolus and examined acute and prolonged effects on feeding and body weight. C75 decreased food intake rapidly and potently at all doses (1-56 nmol) and dose dependently inhibited intake on day 1. Dose-dependent weight loss on day 1 persisted through 4 days of postinjection monitoring. The FAS inhibitor cerulenin produced dose-dependent (560 nmol) hypophagia for 1 day, weight loss for 2 days, and weight regain to vehicle control by day 3. The CPT-1 inhibitor etomoxir (32, 320 nmol) did not alter overall day 1 feeding. However, etomoxir attenuated the hypophagia produced by C75, indicating that CPT-1 stimulation is important for C75's effect. A novel compound, C89b, was characterized in vitro as a selective stimulator of CPT-1 that does not affect fatty acid synthesis. C89b (100, 320 nmol) decreased feeding in mice for 3 days and produced persistent weight loss for 6 days without producing conditioned taste aversion. Similarly, intraperitoneal administration decreased feeding and body weight without producing conditioned taste aversion. These results suggest a role for brain CPT-1 in the regulation of energy balance and implicate CPT-1 stimulation as a pharmacological approach to weight loss.

Glucagon-like peptide-1 (GLP-1) and amylin mediate the feedback control of eating by seemingly separate, but overlapping mechanisms. This study examined the effects of combined doses of the GLP-1 agonist, exendin-4 (Ex-4), and the amylin analog, salmon calcitonin (sCT), on food intake and meal patterns in adult male rhesus monkeys. Monkeys received intramuscular injections of Ex-4 (0, 0.1, 0.32, or 0.56 microg/kg), sCT (0, 0.1, or 0.32 microg/kg), or combinations thereof before a 6-h daily access to food. Dose combinations produced reductions in food intake that were significantly greater than those produced by the individual doses. Surface plots of the hourly intake indicated a synergistic interaction at lower doses of Ex-4 and sCT during the first 4 h of feeding and additive effects at hours 5 and 6. Meal pattern analysis revealed the combinational doses reduced average meal size and meal frequency by additive interactions, whereas infra-additive effects were apparent at lower doses for first meal size. Combinational doses were further characterized by administration of repeated daily injections of 0.56 microg/kg Ex-4 + 0.32 microg/kg sCT for 5 days. This resulted in sustained reductions in daily food intake (>70% from saline baseline) for 5 days with residual reductions ( approximately 48% from saline baseline) persisting on day 1 following the injections. In contrast, when pair-fed an identical amount of daily food, there was a compensatory food intake increase on day 1 following the pair-feeding ( approximately 132% of saline baseline). Such data suggest Ex-4 and sCT interact in an overall additive fashion to reduce food intake and further the understanding of how GLP-1 and amylin agonist combinations influence feeding behavior.

Bello NT, Kemm MH, Moran TH. Salmon calcitonin reduces food intake through changes in meal sizes in male rhesus monkeys.

Background Endogenous testosterone increases with weight loss from diet, exercise, and bariatric surgery. However, little is known about testosterone levels after weight loss from medication. Objectives Uncover the effects of Glucagon‐Like Peptide‐1 receptor agonist (GLP‐1 RA) therapy on serum testosterone. Material and Methods Prospective cohort study of men starting GLP‐1 RA therapy for type 2 diabetes mellitus. Results 51 men lost 2.27 kg (p = 0.00162) and their HbA1c values improved by 0.7% (p = 0.000503) after 6 months of GLP‐1 RA therapy. There was no significant change in testosterone for the group as a whole. However, in subgroup analyses, there was a significant difference in total testosterone change between men starting with baseline total testosterone <320 ng/dL (238.5 ± 56.5 ng/dL to 272.2 ± 82.3 ng/dL) compared to higher values (438 ± 98.2 ng/dL to 412 ± 141.2 ng/dL) (p = 0.0172);free testosterone increased if the baseline total testosterone was <320 ng/dL (55.2 ± 12.8 pg/mL to 57.2 ± 17.6 pg/mL) and decreased if >320 ng/dL (74.7 ± 16.3 pg/mL to 64.2 ± 17.7 pg/mL) (p = 0.00807). Additionally, there were significant differences in testosterone change between men with HbA1c improvements ≥1% (351.6 ± 123.9 ng/dL to 394.4 ± 136.5 ng/dL) compared to men with HbA1c changes <1% (331.8 ± 128.6 ng/dL to 316.1 ± 126.2 ng/dL) (p = 0.0413). Conclusion GLP‐1 RA therapy improves weight and HbA1c without adverse effects on testosterone. Those starting with lower testosterone values or attaining greater improvement in HbA1c may see additional benefits.