Obesity I: Overview and molecular and biochemical mechanisms

Lustig, Robert H.; Collier, David; Kassotis, Christopher D.; Roepke, Troy A.; Kim, Min Ji; Blanc, Étienne; Barouki, Robert; Bansal, Amita; Cave, Matthew C.; Chatterjee, Saurabh; Choudhury, Mahua; Gilbertson, Michael; Lagadic‐Gossmann, Dominique; Howard, Sarah; Lind, Lars; Tomlinson, Craig R.; Vondráček, Jan; Heindel, Jerrold J.

doi:10.1016/j.bcp.2022.115012

Cited by 76 publications

(54 citation statements)

References 407 publications

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“…MetS is also a risk factor, which contributes to the development of T2DM, a mass of visceral adiposity, CVD and mortality [ 9 ]. In addition to these risk factors, obesity and overweight are also related to a proinflammatory and oxidative stress status as a bi-directional process rather than only one-way cause and effect [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of 2-Year Nutritional and Lifestyle Intervention on Oxidative and Inflammatory Statuses in Individuals of 55 Years of Age and over at High Cardiovascular Risk

et al. 2022

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Obesity and overweight are disorders with high impact on the morbidity and mortality of chronic diseases, such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). We aim to assess the effects of 2-year nutritional and lifestyle intervention on oxidative and inflammatory status in individuals of 55 years of age and over at high CVD risk. Participants (n = 100 individuals of 55 years of age and over living in the Balearic Islands, Spain) were randomized into control and intervention group. Anthropometric and haematological parameters, blood pressure and physical activity were measured before and after the intervention. Oxidative and inflammatory biomarkers in plasma, urine, peripheral blood mononuclear cells (PBMCs) and neutrophils were determined. A higher reduction in abdominal obesity, blood pressure and triglycerides levels was observed after a 2-year intervention. An improvement of oxidative stress and proinflammatory status was demonstrated with a significant reduction in myeloperoxidase, xanthine oxidase, malondialdehyde and monocyte chemoattractant protein-1 (MCP1) levels, and an increase in polyphenols in plasma was observed. A decrease in reactive oxygen species production in PBMCs and neutrophils levels after zymosan and lipopolysaccharide activation was found in the intervention group with respect to the control group. The intervention with hypocaloric Mediterranean Diet and customized physical activity improves oxidative stress and proinflammatory status and could contribute to decreasing the CVD risk.

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Section: Introductionmentioning

confidence: 99%

Effects of 2-Year Nutritional and Lifestyle Intervention on Oxidative and Inflammatory Statuses in Individuals of 55 Years of Age and over at High Cardiovascular Risk

et al. 2022

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“…Adipose tissue is now recognized as a highly metabolic organ involved in the regulation of vital physiological functions [54,55]. AT dysfunction has been implicated in systemic metabolic disorders both as a cause and a consequence.…”

Section: Adipose Tissue: An Endocrine Organ Involved In Mo-offspring'...mentioning

confidence: 99%

“…Three AT types exert complementary functions: (i) WAT, mainly adapted for fat storage; (ii) brown AT (BAT), more abundant in newborns, with thermogenic function, given the high mitochondrial content and expression of uncoupling protein 1 (UCP-1); and (iii) beige AT, normally developed upon sympathetic stimulation (e.g., exercise practice, prolonged cold exposure) [55]. Two types are distinguished within the WAT: subcutaneous (SAT) and visceral AT (VAT) [55]. While SAT confers protective effects for energy homeostasis, VAT is associated with IR, high triglyceride content, high blood pressure, and increased metabolic risk [2,56].…”

Section: Adipose Tissue: An Endocrine Organ Involved In Mo-offspring'...mentioning

confidence: 99%

“…Adipokines regulate physiological processes, such as appetite, food intake, immune and inflammatory function, and glucose and lipid metabolism [57]. More than 600 adipokines were already reported, including leptin, adiponectin, resistin, and visfatin [54,55]. Adipokines secreted by ectopic lipid depots, which result from TG storage near internal organs, such as the liver, skeletal muscle, heart, and pancreas, drain to the portal vein, directly impacting liver tissue and cellular function [55].…”

Section: Adipose Tissue: An Endocrine Organ Involved In Mo-offspring'...mentioning

confidence: 99%

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The Endocrine–Metabolic Axis Regulation in Offspring Exposed to Maternal Obesity—Cause or Consequence in Metabolic Disease Programming?

et al. 2022

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Obesity incidence is rising worldwide, including women of reproductive age, contributing to increased gestations in which Maternal Obesity (MO) occurs. Offspring born to obese mothers present an increased predisposition to develop metabolic (e.g., obesity, diabetes) and cardiovascular disease (CVD). The developmental programming of the metabolic dysfunction in MO offspring can initiate in utero. The different availability of metabolic substrates, namely glucose, can modulate cellular growth, proliferation, and differentiation, resulting in different levels of tissue maturation and function. We defined the remodelling of these early processes as the first hit of metabolic disease programming. Among these, adipocyte early differentiation and gut dysbiosis are initial repercussions occurring in MO offspring, contributing to -tissue-specific dysfunction. The second hit of disease programming can be related to the endocrine–metabolic axis dysregulation. The endocrine–metabolic axis consists of multi-organ communication through the release of factors that are able to regulate the metabolic fate of cells of organs involved in physiological metabolic homeostasis. Upon adipose tissue and gut early dysregulation, these organs’ endocrine function can be programmed to the disrupted release of multiple factors (e.g., adiponectin, leptin, glucagon-like peptide). This can be perceived as a natural mechanism to overcome metabolic frailty in an attempt to prevent or postpone organ-specific disease. However, the action of these hormones on other tissues may potentiate metabolic dysfunction or even trigger disease in organs (liver, pancreas, heart) that were also programmed in utero for early disease. A second phase of the endocrine–metabolic dysregulation happens when the affected organs (e.g., liver and pancreas) self-produce an endocrine response, affecting all of the involved tissues and resulting in a new balance of the endocrine–metabolic axis. Altogether, the second hit exacerbates the organ-specific susceptibility to disease due to the new metabolic environment. The developmental programming of the endocrine–metabolic axis can start a vicious cycle of metabolic adaptations due to the release of factors, leading to an endocrine response that can jeopardize the organism’s function. Diseases programmed by MO can be boosted by endocrine dysregulation, namely Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Fatty Pancreas Disease, and the aggravation of the adipose tissue and gut dysfunction. Chronic metabolic dysregulation can also predispose MO offspring to CVD through the modulation of the endocrine environment and/or the metabolic status. To cease the vicious cycle of MO disease transmission among generations and-provide preventive and specialized prenatal and postnatal care to MO offspring, it is necessary to understand the molecular mechanisms underlying the MO-related disease development. In this review, we summarize most of the developmental programming molecular events of the endocrine–metabolic axis described on the offspring exposed to MO, providing a brief overview of the potential mechanisms that predispose MO offspring to metabolic disease, and discuss the programming of the endocrine–metabolic axis as a plausible mechanism for metabolic disease predisposition in MO offspring.

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“…Obesity and its associated comorbidities such as type 2 diabetes mellitus, cardiovascular disease, dyslipidemia and chronic inflammation, among others, have become a global health threat and a major socioeconomic burden for modern societies with a tendency towards sedentary lifestyles and diets based on hypercaloric/ultra-processed food products (Martin-Rodriguez et al, 2015; Khanna et al, 2022; Lustig et al, 2022). Although it is currently well known that significant sex differences exist in the prevalence, incidence and severity of a broad range of diseases, including obesity and obesity-related diabetes and cardiovascular disease (Seidell, 2005; Global et al, 2016; Hales et al, 2020; Teufel et al, 2021; Tsao et al, 2022), these differences are not well understood due to a combination of the lack of inclusion of sex as an influencing factor in preclinical studies and the underrepresentation of women in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Modifier Kdm6a/Utx Controls the Specification of Hypothalamic Neuronal Subtypes in a Sex-Dependent Manner

Zapata

Cambiasso

Arévalo

2022

Preprint

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Kdm6a is an X chromosome-linked H3K27me2/3 demethylase that promotes chromatin accessibility and gene transcription and is critical for tissue/cell-specific differentiation. Previous results showed higher Kdm6a levels in XX than in XY hypothalamic neurons and a female-specific requirement for Kdm6a in mediating increased axogenesis before brain masculinization. Here we explored the sex-specific role of Kdm6a in the specification of neuronal subtypes in the developing hypothalamus. Hypothalamic neuronal cultures were established from sex-segregated E14 mouse embryos and transfected with siRNAs to knockdown Kdm6a expression (Kdm6a-KD). We evaluated by immunofluorescence the effect of Kdm6a-KD on Ngn3, a bHLH transcription factor regulating neuronal sub-specification in hypothalamus. Kdm6a-KD decreased Ngn3 expression in females but not in males, abolishing basal sex differences. Then, we analyzed Kdm6a-KD effect on Ascl1, Pomc, Npy, Sf1, Gad1 and Th expression by RT-qPCR. While Kdm6a-KD downregulated Ascl1 in both sexes equally, we found sex-specific results for Pomc, Npy and Th. Pomc and Th expressed higher in female than in male neurons and Kdm6a-KD reduced their levels only in females, while Npy expressed higher in male than in female neurons and Kdm6a-KD upregulated its expression only in females. Identical results were found by immunofluorescence for Pomc and Npy neuropeptides. Finally, using ChIP-qPCR we found higher H3K27me3 levels at Ngn3, Pomc and Npy promoters in male neurons, in line with Kdm6a higher expression and demethylase activity in females. These results indicate that Kdm6a plays a key sex-specific role in controlling the differentiation of neuronal populations regulating food intake and energy homeostasis.

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Obesity I: Overview and molecular and biochemical mechanisms

Cited by 76 publications

References 407 publications

Effects of 2-Year Nutritional and Lifestyle Intervention on Oxidative and Inflammatory Statuses in Individuals of 55 Years of Age and over at High Cardiovascular Risk

Effects of 2-Year Nutritional and Lifestyle Intervention on Oxidative and Inflammatory Statuses in Individuals of 55 Years of Age and over at High Cardiovascular Risk

The Endocrine–Metabolic Axis Regulation in Offspring Exposed to Maternal Obesity—Cause or Consequence in Metabolic Disease Programming?

Epigenetic Modifier Kdm6a/Utx Controls the Specification of Hypothalamic Neuronal Subtypes in a Sex-Dependent Manner

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