Aims: Emerging evidence suggests that during gestation the in utero environment programs metabolism and can increase risk of obesity in adult offspring. Our aim was to study how alterations in maternal diets during gestation might alter body weight evolution, circulating leptin levels and caloric intake in offspring, leading to changes in body composition. Materials and methods: We fed gestating rats either a control diet (CD), high fat diet (HFD) or an isocaloric low protein diet (LPD), and examined the repercussions in offspring fed similar diets post-weaning on birth weight, body weight evolution, body composition, insulin sensitivity, glucose tolerance and in the relationship between plasma leptin concentration and caloric intake in offspring during growth and development. Key finds: Offspring from dams fed LPD maintained reduced body weight with greater % lean mass and consumed fewer calories despite having leptin levels similar to controls. On the other hand, offspring from dams fed a HFD were insulin resistant and maintained increased body weight and % fat mass, while consuming more calories than controls despite elevated leptin concentrations. Therefore the uterine environment, modulated primarily through maternal nutrition, modified the relationship between circulating leptin levels, body fat, and caloric intake in the offspring, and dams fed a HFD produced offspring with excess adiposity, insulin resistance, and leptin resistance into adulthood. Significance: Our data indicates that in utero environmental factors affected by maternal diet program alterations in the set point around which leptin regulates body weight in offspring into adulthood contributing to obesity.

This study aimed to investigate both the long-term and shortterm impacts of high-fat diets (HFD) or high-sucrose diets (HSD) on the normal diurnal pattern of cognitive function, protein expression, and the molecular clock in mice. Methods: This study used both 6-month and 4-week feeding strategies by providing male C57BL/6J mice access to either a standard chow, HFD, or HSD. Spatial working memory and synaptic plasticity were assessed both day and night, and hippocampal tissue was measured for changes in NMDA and AMPA receptor subunits (GluN2B, GluA1), as well as molecular clock gene expression. Results: HFD and HSD both disrupted normal day/night fluctuations in spatial working memory and synaptic plasticity. Mice fed HFD altered their food intake to consume more calories during the day. Both diets disrupted normal hippocampal clock gene expression, and HFD reduced GluN2B levels in hippocampal tissue. Conclusions: Taken together, these results suggest that both HFD and HSD induce a loss of day/night performance in spatial working memory and synaptic plasticity as well as trigger a cascade of changes that include disruption to the hippocampal molecular clock.

Glucagon (GCG) is an essential regulator of glucose and lipid metabolism that also promotes weight loss. We have shown that glucagon-receptor (GCGR) signaling increases fatty acid oxidation (FAOx) in primary hepatocytes and reduces liver triglycerides in diet-induced obese (DIO) mice; however, the mechanisms underlying this aspect of GCG biology remains unclear. Investigation of hepatic GCGR targets elucidated a potent and previously unknown induction of leptin receptor (Lepr) expression. Liver leptin signaling is known to increase FAOx and decrease liver triglycerides, similar to glucagon action. Therefore, we hypothesized that glucagon increases hepatic LEPR, which is necessary for glucagon-mediated reversal of hepatic steatosis. Eight-week-old control and liver-specific LEPR-deficient mice (LeprΔliver) were placed on a high-fat diet for 12 weeks and then treated with a selective GCGR agonist (IUB288) for 14 days. Liver triglycerides and gene expression were assessed in liver tissue homogenates. Administration of IUB288 in both lean and DIO mice increased hepatic Lepr isoforms a-e in acute (4 hours) and chronic (72 hours,16 days) (P < 0.05) settings. LeprΔliver mice displayed increased hepatic triglycerides on a chow diet alone (P < 0.05), which persisted in a DIO state (P < 0.001), with no differences in body weight or composition. Surprisingly, chronic administration of IUB288 in DIO control and LeprΔliver mice reduced liver triglycerides regardless of genotype (P < 0.05). Together, these data suggest that GCGR activation induces hepatic Lepr expression and, although hepatic glucagon and leptin signaling have similar liver lipid targets, these appear to be 2 distinct pathways.

Glucagon regulates glucose and lipid metabolism and promotes weight loss. Thus, therapeutics stimulating glucagon receptor (GCGR) signaling are promising for obesity treatment; however, the underlying mechanism(s) have yet to be fully elucidated. We previously identified that hepatic GCGR signaling increases circulating fibroblast growth factor 21 (FGF21), a potent regulator of energy balance. We reported that mice deficient for liver Fgf21 are partially resistant to GCGR-mediated weight loss, implicating FGF21 as a regulator of glucagon’s weight loss effects. FGF21 signaling requires an obligate coreceptor (β-Klotho, KLB), with expression limited to adipose tissue, liver, pancreas, and brain. We hypothesized that the GCGR-FGF21 system mediates weight loss through a central mechanism. Mice deficient for neuronal Klb exhibited a partial reduction in body weight with chronic GCGR agonism (via IUB288) compared with controls, supporting a role for central FGF21 signaling in GCGR-mediated weight loss. Substantiating these results, mice with central KLB inhibition via a pharmacological KLB antagonist, 1153, also displayed partial weight loss. Central KLB, however, is dispensable for GCGR-mediated improvements in plasma cholesterol and liver triglycerides. Together, these data suggest GCGR agonism mediates part of its weight loss properties through central KLB and has implications for future treatments of obesity and metabolic syndrome.

Glucagon is an essential regulator of glucose and lipid metabolism that also promotes weight loss. Thus, novel therapeutics that stimulate glucagon-receptor (GcgR) signaling are promising for treatment of obesity and diabetes; however, the mechanism(s) underlying these effects are yet to be fully elucidated. We previously identified that hepatic glucagon signaling increases the secretion of another fasting hormone, Fibroblast Growth Factor 21 (FGF-21), also known to be involved in regulating energy balance. We have recently observed that mice deficient for liver FGF-21 (FGF-21δLiver) are partially resistant to the anti-obesity effects of GcgR agonism, clearly implicating hepatic FGF-21 as an essential component of the glucagon’s weight-loss effects. FGF-21 signals through an obligate co-receptor (βKlotho, Klb), with expression limited to adipose tissue, liver, and brain, specifically within the suprachiasmatic nucleus (SCN) of the hypothalamus and the hindbrain. As the hypothalamus has known roles in regulating energy balance, we hypothesized that the anti-obesity action of the glucagon-FGF-21 system signals through a central mechanism. Mice deficient for neuronal Klb (KlbδCNS) are less susceptible to diet-induced obesity than wild type mice (P<0.01), with no observed differences in food intake or energy expenditure. Following chronic GcgR activation via the selective agonist IUB288, KlbδCNS mice exhibit a partial reduction in body weight (12%) in comparison to control mice (19%), suggesting that FGF-21 mediates glucagon’s anti-obesity properties through central action. Consistent with GcgR-stimulated, neuronal FGF-21 signaling, we found that neuronal activation, measured via immunohistochemical analysis of cFos expression, was increased in the SCN following IUB288 injection. Taken together, these data suggest that glucagon mediates part of its anti-obesity properties through FGF-21-KLB signaling in the SCN, and has implications for future treatments against obesity and the metabolic syndrome. Disclosure S. Nason: None. T. Kim: None. J.P. Antipenko: None. J. Paul: None. B. Finan: Employee; Self; Novo Nordisk Inc. R. DiMarchi: Employee; Self; Novo Nordisk Inc. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc..