Hypocretin/orexin modulates body weight and the metabolism of glucose and insulin

Adeghate, Ernest; Lotfy, Mohamed; D’Souza, Crystal; Alseiari, Saleh; Alsaadi, Abdulla Ali; Qahtan, Saif Abdo

doi:10.1002/dmrr.3229

Cited by 17 publications

(14 citation statements)

References 111 publications

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“…When the effects of all other parameters were excluded by stepwise multiple regression analysis, HOMA-IR was shown to be the first independent predictor of orexin-A (Table -2). This confirms the role of orexin-A in IR and T2DM disease [5,24] and that HOMA-IR is a strong predictor of T2DM development [25].…”

Section: Discussionsupporting

confidence: 76%

Relationship Between Orexin-A and Insulin Resistance in Patients with Type 2 Diabetes Mellitus

Sadiq

Hussein

Maulood

2021

eijs

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Background: Orexin-A is an orexigenic hormone that plays an important role in the metabolism of blood glucose, insulin, and insulin resistance (IR). The pathogenesis of type 2 diabetes mellitus (T2DM) is related to the abnormality in insulin and IR. However, no sufficient studies to date have clearly shown the association of orexin-A with biochemical parameters related to T2DM. Objectives: The aim of this study was to determine the relation of orexin-A with IR and how they associate with physiological changes in T2DM patients. Understanding this relation will offer some pharmacological tools to reduce some complications in diabetes. Materials and Methods: A total of 41 T2DM and 43 non-DM subjects, aged between 40-60 years with body mass index (BMI) ≤25 kg/m2, participated in the present study. Fasting serum orexin-A, IR, fasting blood glucose (FBG), glycated hemoglobin (HbA1C), lipid profile, liver enzymes (alanine aminotransferase (ALT) and aspartate transaminase (AST)), nitric oxide (NO), and malondialdehyde (MDA) parameters were evaluated. Orexin-A was evaluated by using enzyme-linked immunosorbent assay (ELISA). For statistical analysis, GraphPad Prism 7.0 and SPSS version 24.0 programs were used. Results: Orexin-A was positively correlated with blood pressure, FBG, HbA1c, insulin, and IR but inversely related to insulin sensitivity (IS), leptin, and gender. Stepwise multiple regression presented HOMA-IR, diastolic blood pressure, and very-low-density lipoprotein-cholesterol as predictors for orexin-A. The area under control value showed orexin-A, FBG, HbA1c, HOMA-IR, IS, ALT, AST, NO and MDA as biomarkers for T2DM disease. Conclusion: Orexin-A has a predictive ability to diagnose T2DM, as it is significantly associated with hyperglycemia, IR, and IS.

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Section: Discussionsupporting

confidence: 76%

Relationship Between Orexin-A and Insulin Resistance in Patients with Type 2 Diabetes Mellitus

Sadiq

Hussein

Maulood

2021

eijs

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“…However, as we have previously shown that obese phenotype was caused by increased food intake, we speculate that the silencing of the IKKβ expression prohibited hyperphagiainduced obesity in HD mice. The orexin and A13 TH neuronal populations are involved in metabolism regulation (Adeghate et al, 2020;Shi et al, 2013) and they are affected in HD (Gabery et al, 2010;Hult et al, 2011;Petersen et al, 2005;Soylu-Kucharz et al, 2015). As the inactivation of the IKKβ signaling did not affect the preservation of these cells, we can speculate that orexin and A13 TH neuropathology are not the central cell populations responsible for the development of HD bodyweight alterations.…”

Section: Discussionmentioning

confidence: 94%

IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington’s disease mouse model

Soylu-Kucharz

Khoshnan

Petersén

2021

Preprint

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Background: Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, and underlying mechanisms are not fully known. As the IKKβ/NF-kB pathway is an essential regulator of metabolism, we investigated the involvement of IKKβ, the upstream activator of NF-kB in hypothalamus-specific HD metabolic changes. Methods: Using viral vectors, we expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) fragments in the hypothalamus of mice without IKKβ in the CNS (IKKβ-/-) and control mice (IKKβ+/+). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology. Results: Hypothalamic expression of mHTT led to an obese phenotype only in female mice. CNS-specific inactivation of IKKβ prohibited weight gain in females, which was independent of neuroprotection and microglial activation. Conclusions: The expression of mHTT in the hypothalamus causes metabolic imbalance in a sex-specific fashion, and central inhibition of the IKKβ pathway attenuates the obese phenotype.

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“…When the serum level of leptin is high for a long period of time, the hypothalamic neurons do not really sense that information any more. The brain thinks that the person is still hungry, thereby eating more to reach the point of satiety leads to developing obesity [44,45]. This will make the obesity even more severe.…”

Section: Obesity and Hormones Regulating Food Intake And Satietymentioning

confidence: 99%

Obesity: Molecular Mechanisms, Epidemiology, Complications and Pharmacotherapy

Jaberi

Cohen

Saeed

et al. 2021

Advances in Biochemistry in Health and Disease

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Obesity is a common disorder affecting millions of people worldwide. The number of overweight and obese subjects, globally, is currently 2 billion and 800 million, respectively. Projected estimates show that the number of overweight citizens will approach 60% of the world's population by the year 2030. Oxidative stress facilitates the development of obesity by stimulating pre-adipocyte differentiation and eventual adipose accumulation. Large deposits of fat release excessive quantities of adipocytokines, resulting in chronic inflammation. The obesity-induced chronic inflammation paves the way for a large variety of systemic complications including but not limited to diabetes mellitus, hyperlipidemia, atherosclerotic lesions, cardiovascular diseases tissue and malignancy. In addition, other obesity-inducers, such as increased insulin growth factor 1, insulin resistance, and increased tissue level of leptin and low concentration of adiponectin may lead to the development of tissue malignancy. Increased physical activity coupled with a healthy food intake is crucial to the management of obesity. Anti-obesity drugs such as sibutramine, qsymia (a combination of phentermine and topiramate), and orlistat have been used to treat obesity with variable degrees of efficacy. Bariatric surgery becomes a choice in severe cases when physical activity and pharmacotherapy fail. In the obese patient with diabetes mellitus, the choice of hypoglycemic agent is important. Metformin,

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Hypocretin/orexin modulates body weight and the metabolism of glucose and insulin

Cited by 17 publications

References 111 publications

Relationship Between Orexin-A and Insulin Resistance in Patients with Type 2 Diabetes Mellitus

Relationship Between Orexin-A and Insulin Resistance in Patients with Type 2 Diabetes Mellitus

IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington’s disease mouse model

Obesity: Molecular Mechanisms, Epidemiology, Complications and Pharmacotherapy

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