The discovery of leptin was intrinsically associated with its ability to regulate body weight. However, the effects of leptin are more far-reaching and include profound glucose-lowering and anti-lipogenic effects, independent of leptin’s regulation of body weight. Regulation of glucose metabolism by leptin is mediated both centrally and via peripheral tissues and is influenced by the activation status of insulin signaling pathways. Ectopic fat accumulation is diminished by both central and peripheral leptin, an effect that is beneficial in obesity-associated disorders. The magnitude of leptin action depends upon the tissue, sex, and context being examined. Peripheral tissues that are of particular relevance include the endocrine pancreas, liver, skeletal muscle, adipose tissues, immune cells, and the cardiovascular system. As a result of its potent metabolic activity, leptin is used to control hyperglycemia in patients with lipodystrophy and is being explored as an adjunct to insulin in patients with type 1 diabetes. In order to fully understand the role of leptin in physiology and to maximize its therapeutic potential, the mechanisms of leptin action in these tissues needs to be further explored.

Obesity arises from disrupted energy balance and is caused by chronically higher energy intake compared to expenditure via basal metabolic rate, exercise, and thermogenesis. The brown adipose tissue (BAT), the primary thermogenic organ, has received considerable attention as a potential therapeutic target due to its ability to burn lipids in the production of heat. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been identified as a key regulator of the physiological stress response both centrally and peripherally. While PACAP has been shown to increase thermogenesis by acting at the hypothalamus to increase sympathetic output to BAT, a peripheral role for PACAP-activated thermogenesis has not been studied. We identified PACAP receptor (PAC1, VPAC1/2) expression for the first time in murine BAT and confirmed their expression in white adipose tissues. PAC1 receptor expression was significantly altered in all three adipose tissues studied in response to 3.5-week cold acclimation, with expression patterns differing by depot type. In primary cell culture, VPAC1 was increased in differentiated compared to non-differentiated brown adipocytes, and the same trend was observed for the PACAP-specific receptor PAC1 in gonadal white fat primary cultures. The primary PAC1R mRNA splice variant in interscapular BAT was determined as isoform 2 by RNA-Seq. These results show that PACAP receptors are present in adipose tissues and may have important functional roles in adipocyte differentiation, lipid metabolism, or adipose sensitization to sympathetic signaling in response to thermogenic stimuli.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide critical to the regulation of the stress response, including a role in energy homeostasis. Mice lacking PACAP are cold sensitive and have impaired adrenergic-induced thermogenesis. Interestingly, Pacap null mice can survive cold housing if acclimated slowly, similar to observations in UCP1 deficient mice. We hypothesized that Pacap null mice employ alternate thermogenic pathways to compensate for impaired adaptive thermogenesis in male and female, Pacap-/- and Pacap+/+ mice acclimated to cold. Observations of behaviour and assessment of fibre type in skeletal muscles did not show evidence of prolonged burst shivering or changes in oxidative metabolism in male or female Pacap-/- mice during cold acclimation compared to Pacap+/+ mice.​ Despite previous work that has established impaired capacity for adaptive thermogenesis in Pacap null mice, adaptive thermogenesis can be induced in mice lacking PACAP to support survival with cold housing. Interestingly, sex-specific morphological and molecular differences in adipose tissue remodelling were observed in Pacap null mice compared to controls. Thus, sexual dimorphisms are highlighted in adipose tissue remodelling and thermogenesis with cold acclimation in the absence of PACAP.

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Although innate immunity is linked to metabolic health, the effect of leptin signaling in cells from the innate immune system on glucose homeostasis has not been thoroughly investigated. We generated two mouse models using Cre-lox methodology to determine the effect of myeloid cell-specific leptin receptor (Lepr) reconstitution and Lepr knockdown on in vivo glucose metabolism. Male mice with myeloid cell-specific Lepr reconstitution (Lyz2Cre+LeprloxTB/loxTB) had better glycemic control as they aged compared to male mice with whole-body transcriptional blockade of Lepr (Lyz2Cre−LeprloxTB/loxTB). In contrast, Lyz2Cre+LeprloxTB/loxTB females only had a trend for diminished hyperglycemia after a prolonged fast. During glucose tolerance tests, Lyz2Cre+LeprloxTB/loxTB males had a mildly improved plasma glucose profile compared to Cre− controls while Lyz2Cre+LeprloxTB/loxTB females had a similar glucose excursion to their Cre− controls. Myeloid cell-specific Lepr knockdown (Lyz2Cre+Leprflox/flox) did not significantly alter body weight, blood glucose, insulin sensitivity, or glucose tolerance in males or females. Expression of the cytokine interleukin 10 (anti-inflammatory) tended to be higher in adipose tissue of male Lyz2Cre+LeprloxTB/loxTB mice (p = 0.0774) while interleukin 6 (pro-inflammatory) was lower in male Lyz2Cre+Leprflox/flox mice (p < 0.05) vs. their respective controls. In conclusion, reconstitution of Lepr in cells of myeloid lineage has beneficial effects on glucose metabolism in male mice.