Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity.

The mechanisms underlying obesity-induced insulin resistance remain incompletely understood, as impaired cellular insulin signaling, traditionally considered the primary driver of insulin resistance, does not always accompany impaired insulin action. Overnutrition rapidly increases plasma norepinephrine (NE), suggesting overactivation of the sympathetic nervous system (SNS). However, the role of the SNS in obesity is controversial, as both increased and decreased SNS activity (SNA) have been reported.

Why do some individuals with obesity remain metabolically healthy?

A recent study by Peterson et al. that characterized individuals with metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUO) in depth provides insights into the potential pathogenesis of MUO that accounts for much of the cardiometabolic disease and excess mortality caused by the obesity epidemic.

Sympathetic overdrive and unrestrained adipose lipolysis drive alcohol-induced hepatic steatosis in rodents.

Objective: Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow.

Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway.

Objectives: Insulin's ability to counterbalance catecholamine-induced lipolysis defines insulin action in adipose tissue. Insulin suppresses lipolysis directly at the level of the adipocyte and indirectly through signaling in the brain. Here, we further characterized the role of brain insulin signaling in regulating lipolysis and defined the intracellular insulin signaling pathway required for brain insulin to suppress lipolysis.

Use of Patient-Reported Outcomes for Assessing Diabetes Outcomes.

The treatment of diabetes can be complex and overwhelming for patients as it demands persistent attention to lifestyle management, adherence to medications, monitoring of side effects of drugs, and management of devices for glucose monitoring and/or insulin infusion. Therefore, understanding patient-reported outcomes (PROs) that provide direct insight into the patient's experience with diabetes is crucial for optimizing diabetes management.This review provides an overview of commonly used PRO questionnaires that assess different aspects of diabetes management.

Brain insulin signalling in metabolic homeostasis and disease.

Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.

Beneficial metabolic role of β-arrestin-1 expressed by AgRP neurons.

β-Arrestin-1 and β-arrestin-2 have emerged as important signaling molecules that modulate glucose fluxes in several peripheral tissues. The potential roles of neuronally expressed β-arrestins in regulating glucose homeostasis remain unknown. We here report that mice lacking β-arrestin-1 (barr1) selectively in AgRP neurons displayed impaired glucose tolerance and insulin sensitivity when consuming an obesogenic diet, while mice overexpressing barr1 selectively in AgRP neurons were protected against obesity-associated metabolic impairments.

Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis.

Hepatic steatosis develops when lipid influx and production exceed the liver's ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism.

Fat cells gobbling up norepinephrine?

The sympathetic nervous system (SNS) controls key aspects of adipose tissue (AT) function through the release of norepinephrine (NE) and beta adrenergic signaling. Sympathetic tone is determined by NE release but also by the rate of extracellular NE clearance that historically has been believed to occur solely through solute carrier family 6 member 2 (SLC6A2) expressed on sympathetic neurons. Song and colleagues show that adipocytes can also clear NE through organic cation transporter 3 (Oct3).

Active Cushing Disease Is Characterized by Increased Adipose Tissue Macrophage Presence.

Context: Although glucocorticoids (GCs) have potent anti-inflammatory actions, patients with hypercortisolism due to Cushing disease (CD) have increased circulating proinflammatory cytokines that may contribute to their insulin resistance and cardiovascular disease. The mechanisms and tissues that account for the increased systemic inflammation in patients with CD are unknown.

Objective: To determine whether chronic endogenous GC exposure due to CD is associated with adipose tissue (AT) inflammation in humans.

iPSC-derived familial Alzheimer's PSEN2 cholinergic neurons exhibit mutation-dependent molecular pathology corrected by insulin signaling.

Background: Type 2 diabetes (T2D) is a recognized risk factor for the development of cognitive impairment (CI) and/or dementia, although the exact nature of the molecular pathology of T2D-associated CI remains obscure. One link between T2D and CI might involve decreased insulin signaling in brain and/or neurons in either animal or postmortem human brains as has been reported as a feature of Alzheimer's disease (AD). Here we asked if neuronal insulin resistance is a cell autonomous phenomenon in a familial form of AD.

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums.

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs.

Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling.

Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of glucokinase is unknown, and clinically, as inhibition of glucose production is predicted to increase lipogenesis.

Germline deletion of Krüppel-like factor 14 does not increase risk of diet induced metabolic syndrome in male C57BL/6 mice.

Objective: The transcription factor Krüppel-like factor 14 (KLF14) has been associated with type 2 diabetes and high-density lipoprotein-cholesterol (HDL-C) through genome-wide association studies. The mechanistic underpinnings of KLF14's control of metabolic processes remain largely unknown. We studied the physiological roles of KLF14 in a knockout (KO) mouse model.

Blocking FSH induces thermogenic adipose tissue and reduces body fat.

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the β-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr.

Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis.

Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue.

Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action.

Insulin is a key regulator of adipose tissue lipolysis, and impaired adipose tissue insulin action results in unrestrained lipolysis and lipotoxicity, which are hallmarks of the metabolic syndrome and diabetes. Insulin regulates adipose tissue metabolism through direct effects on adipocytes and through signaling in the central nervous system by dampening sympathetic outflow to the adipose tissue. Here we examined the role of insulin signaling in agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons in regulating hepatic and adipose tissue insulin action.

Chronic Intranasal Insulin Does Not Affect Hepatic Lipids but Lowers Circulating BCAAs in Healthy Male Subjects.

Context: Nonalcoholic fatty liver disease and elevated circulating branched-chain amino acids (BCAAs) are common characteristics of obesity and type 2 diabetes. In rodents, brain insulin signaling controls both hepatic triglyceride secretion and BCAA catabolism. Whether brain insulin signaling controls similar metabolic pathways in humans is unknown.

How does leptin restore euglycemia in insulin-deficient diabetes?

Insulin replacement is the cornerstone of type 1 diabetes (T1D) treatment; however, glycemic control remains a challenge. Leptin has been shown to effectively restore euglycemia in rodent models of T1D; however, the mechanism or mechanisms by which leptin exerts glycemic control are unclear. In this issue of the JCI, Perry and colleagues provide evidence that suppression of lipolysis is a key facet of leptin-mediated restoration of euglycemia.

Embryonic ablation of neuronal VGF increases energy expenditure and reduces body weight.

Germline ablation of VGF, a secreted neuronal, neuroendocrine, and endocrine peptide precursor, results in lean, hypermetabolic, and infertile adult mice that are resistant to diet-, lesion-, and genetically-induced obesity and diabetes (Hahm et al., 1999, 2002). To assess whether this phenotype is predominantly driven by reduced VGF expression in developing and/or adult neurons, or in peripheral endocrine and neuroendocrine tissues, we generated and analyzed conditional VGF knockout mice, obtained by mating loxP-flanked (floxed) Vgf mice with either pan-neuronal Synapsin-Cre- or forebrain alpha-CaMKII-Cre-recombinase-expressing transgenic mice.

Perinatal DDT Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice.

Background: Dichlorodiphenyltrichloroethane (DDT) was used extensively to control malaria, typhus, body lice, and bubonic plague worldwide, until countries began restricting its use in the 1970s. However, the use of DDT to control vector-borne diseases continues in developing countries. Prenatal DDT exposure is associated with elevated blood pressure in humans.

Proinflammatory cytokines remain elevated despite long-term remission in Cushing's disease: a prospective study.

Context: Inflammation contributes to the development of metabolic and cardiovascular disease. Cushing's disease (CD), a state of chronic glucocorticoid (GC) excess characterized by visceral obesity and insulin resistance, may be associated with increased systemic inflammation. Cardiovascular mortality in CD remains elevated even after successful remission.

Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer's disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels.

Introduction: Epidemiologic studies have demonstrated an association between diabetes and dementia. Insulin signaling within the brain, in particular within the hypothalamus regulates carbohydrate, lipid, and branched chain amino acid (BCAA) metabolism in peripheral organs such as the liver and adipose tissue. We hypothesized that cerebral amyloidosis impairs central nervous system control of metabolism through disruption of insulin signaling in the hypothalamus, which dysregulates glucose and BCAA homeostasis resulting in increased susceptibility to diabetes.

Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer's APP/PSEN1 mice by gene targeting of diabetes/Alzheimer's-related Sorcs1.

Introduction: Insulin resistance and type 2 diabetes mellitus (T2D) are associated with increased risk for cognitive impairment, Alzheimer's disease (AD) and vascular dementia. SORCS1 encodes a protein-sorting molecule genetically linked to both T2D and AD. The association of SORCS1 with both AD and T2D is sexually dimorphic in humans, with both disease associations showing more robust effects in females.

Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain.

Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk.