Deficiency of Irx5 protects mice from diet-induced obesity and associated metabolic abnormalities

Obesity, a leading cause of several metabolic abnormalities, is mainly due to an imbalance of energy homeostasis. IRX3 and IRX5 have been suggested as determinants of obesity in connection with the intronic variants of FTO, the strongest genetic risk factor of polygenic obesity in humans. Although the causal effects of Irx3 on obesity and its related metabolic consequences have been demonstrated in vivo, the metabolic function of Irx5 remains unclear. In this study, using mice homozygous for an Irx5-knockout (Irx5KO) allele, we show a direct link between Irx5 expression and regulation of body mass/composition and energy homeostasis. Irx5KO mice are leaner and resistant to diet-induced obesity and associated metabolic abnormalities, primarily through the loss of adiposity with an increase in basal metabolic rate with adipose thermogenesis and lower food intake. Furthermore, our long-term feeding analysis found that Irx3 mutant mouse lines also have less food intake, indicating that lower caloric intake also contributes to their lean phenotype. Together, these results demonstrate that Irx5 is critical for energy homeostasis and regulation of body mass/composition and suggest that it likely acts in other tissues beyond adipocytes.

Leptin Receptor Blockade Attenuates Hypertension, but Does Not Affect Ventilatory Response to Hypoxia in a Model of Polygenic Obesity

BackgroundObesity can cause hypertension and exacerbates sleep-disordered breathing (SDB). Leptin is an adipocyte-produced hormone, which increases metabolic rate, suppresses appetite, modulates control of breathing, and increases blood pressure. Obese individuals with high circulating levels of leptin are resistant to metabolic and respiratory effects of leptin, but they appear to be sensitive to hypertensive effects of this hormone. Obesity-induced hypertension has been associated with hyperleptinemia. New Zealand obese (NZO) mice, a model of polygenic obesity, have high levels of circulating leptin and hypertension, and are prone to develop SDB, similarly to human obesity. We hypothesize that systemic leptin receptor blocker Allo-aca will treat hypertension in NZO mice without any effect on body weight, food intake, or breathing.MethodsMale NZO mice, 12–13 weeks of age, were treated with Allo-aca (n = 6) or a control peptide Gly11 (n = 12) for 8 consecutive days. Doses of 0.2 mg/kg were administered subcutaneously 2×/day, at 10 AM and 6 PM. Blood pressure was measured by telemetry for 48 h before and during peptide infusion. Ventilation was assessed by whole-body barometric plethysmography, control of breathing was examined by assessing the hypoxic ventilatory response (HVR), and polysomnography was performed during light-phase at baseline and during treatment. Heart rate variability analyses were performed to estimate the cardiac autonomic balance.ResultsSystemic leptin receptor blockade with Allo-aca did not affect body weight, body temperature, and food intake in NZO mice. Plasma levels of leptin did not change after the treatment with either Allo-aca or the control peptide Gy11. NZO mice were hypertensive at baseline and leptin receptor blocker Allo-aca significantly reduced the mean arterial pressure from 134.9 ± 3.1 to 124.9 ± 5.7 mmHg during the light phase (P < 0.05), whereas the control peptide had no effect. Leptin receptor blockade did not change the heart rate or cardiac autonomic balance. Allo-aca did not affect minute ventilation under normoxic or hypoxic conditions and HVR. Ventilation, apnea index, and oxygen desaturation during NREM and REM sleep did not change with leptin receptor blockade.ConclusionSystemic leptin receptor blockade attenuates hypertension in NZO mice, but does not exacerbate obesity and SDB. Thus, leptin receptor blockade represents a potential pharmacotherapy for obesity-associated hypertension.

Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Leptin influences food intake by informing the brain about the status of body fat stores. Rare <i>LEP</i> mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in <i>LEP, ZNF800, KLHL31</i>, and <i>ACTL9</i>, and one intergenic variant near <i>KLF14.</i> The missense variant Val94Met (rs17151919) in <i>LEP</i> was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10^-16, n=3,901). Using <i>in vitro</i> analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Leptin influences food intake by informing the brain about the status of body fat stores. Rare <i>LEP</i> mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in <i>LEP, ZNF800, KLHL31</i>, and <i>ACTL9</i>, and one intergenic variant near <i>KLF14.</i> The missense variant Val94Met (rs17151919) in <i>LEP</i> was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10^-16, n=3,901). Using <i>in vitro</i> analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

Relative adipose tissue failure in Alström syndrome drives obesity-induced insulin resistance

Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinaemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative adipose tissue failure in monogenic obese cohort; a finding supported by observations in a novel conditional mouse model (<i>Alms^flin/flin</i>) and ALMS1-silenced human primary adipocytes. Whereas, selective reactivation of ALMS1 gene in adipose tissue of an ALMS conditional knockdown mice model (<i>Alms^flin/flin;Adipo-Cre^+/-</i>) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative adipose tissue failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte driven insulin resistance may assist development of adipose tissue targeted therapeutic strategies for diabetes.

Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Leptin influences food intake by informing the brain about the status of body fat stores. Rare <i>LEP</i> mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in <i>LEP, ZNF800, KLHL31</i>, and <i>ACTL9</i>, and one intergenic variant near <i>KLF14.</i> The missense variant Val94Met (rs17151919) in <i>LEP</i> was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10^-16, n=3,901). Using <i>in vitro</i> analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

Physical Activity Might Reduce the Adverse Impacts of the FTO Gene Variant rs3751812 on the Body Mass Index of Adults in Taiwan

The fat mass and obesity-associated (FTO) gene is a significant genetic contributor to polygenic obesity. We investigated whether physical activity (PA) modulates the effect of FTO rs3751812 on body mass index (BMI) among Taiwanese adults. Analytic samples included 10,853 Taiwan biobank participants. Association of the single-nucleotide polymorphism (SNP) with BMI was assessed using linear regression models. Physical activity was defined as any kind of exercise lasting 30 min each session, at least three times a week. Participants with heterozygous (TG) and homozygous (TT) genotypes had higher BMI compared to those with wild-type (GG) genotypes. The β value was 0.381(p < 0.0001) for TG individuals and 0.684 (p = 0.0204) for TT individuals. There was a significant dose-response effect among carriers of different risk alleles (p trend <0.0001). Active individuals had lower BMI than their inactive counterparts (β = −0.389, p < 0.0001). Among the active individuals, significant associations were found only with the TG genotype (β = 0.360, p = 0.0032). Inactive individuals with TG and TT genotypes had increased levels of BMI compared to those with GG genotypes: Their β values were 0.381 (p = 0.0021) and 0.950 (p = 0.0188), respectively. There was an interaction between the three genotypes, physical inactivity, and BMI (p trend = 0.0002). Our data indicated that increased BMI owing to genetic susceptibility by FTO rs3751812 may be reduced by physical activity.