Resistance to Diet-Induced Obesity and Associated Metabolic Perturbations in Haploinsufficient Monocarboxylate Transporter 1 Mice

The monocarboxylate transporter 1 (MCT1 or SLC16A1) is a carrier of short-chain fatty acids, ketone bodies, and lactate in several tissues. Genetically modified C57BL/6J mice were produced by targeted disruption of the mct1 gene in order to understand the role of this transporter in energy homeostasis. Null mutation was embryonically lethal, but MCT1(+/-) mice developed normally. However, when fed high fat diet (HFD), MCT1(+/-) mice displayed resistance to development of diet-induced obesity (24.8% lower body weight after 16 weeks of HFD), as well as less insulin resistance and no hepatic steatosis as compared to littermate MCT1(+/+) mice used as controls. Body composition analysis revealed that reduced weight gain in MCT1(+/-) mice was due to decreased fat accumulation (50.0% less after 9 months of HFD) notably in liver and white adipose tissue. This phenotype was associated with reduced food intake under HFD (12.3% less over 10 weeks) and decreased intestinal energy absorption (9.6% higher stool energy content). Indirect calorimetry measurements showed similar to 15% increase in O-2 consumption and CO2 production during the resting phase, without any changes in physical activity. Determination of plasma concentrations for various metabolites and hormones did not reveal significant changes in lactate and ketone bodies levels between the two genotypes, but both insulin and leptin levels, which were elevated in MCT1(+/+) mice when fed HFD, were reduced in MCT1(+/-) mice under HFD. Interestingly, the enhancement in expression of several genes involved in lipid metabolism in the liver of MCT1(+/+) mice under high fat diet was prevented in the liver of MCT1(+/-) mice under the same diet, thus likely contributing to the observed phenotype. These findings uncover the critical role of MCT1 in the regulation of energy balance when animals are exposed to an obesogenic diet.

The role of the transcriptional regulator BCL6 in adipose tissue development and remodeling

Teresa Didonna

The adipose tissue is increasingly recognized for the important role it plays in various diseases and pathological conditions, such as obesity, diabetes, cardiovascular diseases, osteoporosis, cancer, and aging. Despite its long-held reputation for being a simple fat storage tissue, we now know the adipose tissue is a singular organ playing a crucial role in whole-body metabolism and energy homeostasis. Understanding the development and functioning of adipose tissue and, in particular, of its structural and functional fat depots, is crucial to understanding human health and disease, and can pave the way for personalized therapeutic and preventive approaches. Transcription factors are key regulators of adipose tissue biogenesis, development, and responses to changes in environmental stimuli such as feeding, fasting, and exercise. The transcription repressor BCL6 - well known in immunology and cancer - has been recently linked to adipogenesis and metabolism. In the context of this thesis, in order to better understand the role of BCL6 in adipose tissue development and remodeling, we sought to further investigate the physiological function of BCL6 in white and brown adipose tissue. We developed and characterized a fat-specific conditional knockout mouse model for Bcl6 (Bcl6 FKO), and a Pdgfra-Cre driver was used to obtain in vivo ablation of Bcl6 in adipogenic precursors and stem cells (ASPCs). We discovered that ablation of Bcl6 in adipocyte precursors has a major impact on white fat mass and its distribution in the bodies of mice. Moreover, being fed a standard and a high-fat diet has a prominent effect on visceral adipose tissue, the mass of which was significantly reduced compared to that of control mice. Additionally, Bcl6 FKO mice did not demonstrate sensitivity to high-fat diet-induced mass gain and related comorbidities, such as hepatic steatosis and glucose-homeostasis alterations. The increased number of adipocytes observed in the gonadal adipose tissue occurred without increasing overall adiposity and body weight compared to control mice under a high-caloric diet regime. In conclusion, Bcl6 FKO mice represent a lean mouse model with a healthy balance between subcutaneous and visceral white adipose tissue depots. BCL6 could be an interesting adipose-specific target for therapeutic interventions in the context of obesity and related metabolic dysfunctions.

EPFL2019

Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis

Johan Auwerx, Dongryeol Ryu

Reduced mitochondria! electron transport chain activity promotes longevity and improves energy homeostasis via cell-autonomous and non-autonomous factors in multiple model systems. This mitohormetic effect is thought to involve the mitochondrial unfolded protein response (UPRmt), an adaptive stress-response pathway activated by mitochondria' proteotoxic stress. Using mice with skeletal muscle specific deficiency of Crifl (muscle-specific knockout [MKO]), an integral protein of the large mitoribosomal subunit (39S), we identified growth differentiation factor 15 (GDF15) as a UPRmt-associated cell non-autonomous myomitokine that regulates systemic energy homeostasis. MKO mice were protected against obesity and sensitized to insulin, an effect associated with elevated GDF15 secretion after UPRmt activation. In ob/ob mice, administration of recombinant GDF15 decreased body weight and improved insulin sensitivity, which was attributed to elevated oxidative metabolism and lipid mobilization in the liver, muscle, and adipose tissue. Thus, GDF15 is a potent mitohormetic signal that safeguards against the onset of obesity and insulin resistance.

Rockefeller Univ Press2017

Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response

Johan Auwerx, Jun Yong Kim

Perturbation of mitochondrial proteostasis provokes cell autonomous and cell non-autonomous responses that contribute to homeostatic adaptation. Here, we demonstrate distinct metabolic effects of hepatic metabokines as cell non-autonomous factors in mice with mitochondrial OxPhos dysfunction. Liver-specific mitochondrial stress induced by a loss-of-function mutation in Crif1 (LKO) leads to aberrant oxidative phosphorylation and promotes the mitochondrial unfolded protein response. LKO mice are highly insulin sensitive and resistant to diet-induced obesity. The hepatocytes of LKO mice secrete large quantities of metabokines, including GDF15 and FGF21, which confer metabolic benefits. We evaluated the metabolic phenotypes of LKO mice with global deficiency of GDF15 or FGF21 and show that GDF15 regulates body and fat mass and prevents diet-induced hepatic steatosis, whereas FGF21 upregulates insulin sensitivity, energy expenditure, and thermogenesis in white adipose tissue. This study reveals that the mitochondrial integrated stress response (ISRmt) in liver mediates metabolic adaptation through hepatic metabokines.

CELL PRESS2021

The role of the transcriptional regulator BCL6 in adipose tissue development and remodeling

Teresa Didonna

EPFL2019