Parathyroid hormone enhances appetite and fails to reduce adiposity in ob/ob mice.

Obesity is a major driver of type 2 diabetes, underscoring the urgent need for therapies that target both energy expenditure and glucose homeostasis. Parathyroid hormone (PTH) has been implicated in promoting adipose tissue browning and thermogenesis, but its metabolic impact in the context of obesity remains uncertain. We aimed to examine the effects of PTH in ob/ob mice, a leptin-deficient model of obesity and diabetes. A single dose or daily injections of human PTH(1-34) were administered to ob/ob mice and their wild-type littermates. Metabolic outcomes, adipose tissue thermogenesis, and appetite-regulating pathways were assessed. A pair-feeding study was also performed to isolate the effect of PTH from food intake. A single acute dose of PTH upregulated thermogenic gene expression in adipose tissue in a dose-dependent manner. However, repeated daily PTH administration failed to sustain adipose browning or improve insulin resistance and hyperglycemia; instead, it exacerbated weight gain, primarily due to increased food intake. Mechanistically, PTH enhanced gastric ghrelin production and upregulated hypothalamic AgRP expression, suggesting a central orexigenic effect. In pair-feeding experiments, PTH-treated mice showed no significant improvements in adiposity or metabolic parameters, even when caloric intake was matched. Although PTH transiently promotes thermogenesis in adipose tissue in ob/ob mice, sustained exposure exacerbates hyperphagia without meaningful metabolic benefit. These findings highlight the challenges of targeting PTH signaling for treating obesity-related diabetes.