Obesity, diabetes and metabolic syndrome result from complex interactions between genetic and environmental factors, including the gut microbiota. To dissect these interactions, we utilized three commonly-used inbred strains of mice – obesity/diabetes-prone C57Bl/6J mice, obesity/diabetes-resistant 129S1/SvImJ, from Jackson Laboratory and obesity-prone, but diabetes resistant 129S6/SvEvTac from Taconic - plus three derivative lines generated by breeding these strains in a new, common environment. Analysis of metabolic parameters and gut microbiota in all strains and their environmentally-normalized derivatives revealed strong interactions between microbiota, diet, breeding site and metabolic phenotype. Strain-dependent and strain-independent correlations were found between specific microbiota and phenotypes, some of which could be transferred to germ-free recipient animals by fecal transplantation. Environmental reprogramming of microbiota resulted in 129S6/SvEvTac becoming obesity-resistant. Thus, development of obesity/metabolic syndrome is the result of interactions between gut microbiota, host genetics and diet. In permissive genetic backgrounds, environmental reprograming of microbiota can ameliorate development of metabolic syndrome.

Diabetes and insulin resistance are associated with altered brain imaging, depression, and increased rates of age-related cognitive impairment. Here we demonstrate that mice with a brain-specific knockout of the insulin receptor (NIRKO mice) exhibit brain mitochondrial dysfunction with reduced mitochondrial oxidative activity, increased levels of reactive oxygen species, and increased levels of lipid and protein oxidation in the striatum and nucleus accumbens. NIRKO mice also exhibit increased levels of monoamine oxidase A and B (MAO A and B) leading to increased dopamine turnover in these areas. Studies in cultured neurons and glia cells indicate that these changes in MAO A and B are a direct consequence of loss of insulin signaling. As a result, NIRKO mice develop age-related anxiety and depressive-like behaviors that can be reversed by treatment with MAO inhibitors, as well as the tricyclic antidepressant imipramine, which inhibits MAO activity and reduces oxidative stress. Thus, insulin resistance in brain induces mitochondrial and dopaminergic dysfunction leading to anxiety and depressive-like behaviors, demonstrating a potential molecular link between central insulin resistance and behavioral disorders. A s life expectancy in humans has increased, we are faced with a worldwide epidemic of age-related diseases such as type 2 diabetes (T2D) and Alzheimer's disease (1). These parallel epidemics may not be coincidental. Indeed, studies have demonstrated an association between diabetes and a variety of brain alterations including depression, age-related cognitive decline, Alzheimer's disease, and Parkinson's disease (2, 3). In addition, individuals with both type 1 and type 2 diabetes have been shown to have a variety of abnormalities in brain imaging, including altered brain activity and connectivity by functional MRI (4, 5), altered microstructure by diffusion tensor imaging (6, 7), and altered neuronal circuitry in the striatum (8). Conversely, patients with Alzheimer's disease show signs of central insulin resistance with increased insulin receptor substrate (IRS) 1 serine phosphorylation in the brain and decreased insulin concentrations in the cerebrospinal fluid (9, 10). Furthermore, pilot clinical trials of intranasal insulin administered to individuals with Alzheimer's disease suggest decreased rates of cognitive decline (11).These observations in humans have been mechanistically supported by studies in rodents and cultured cells, which have shown that insulin receptor signaling in brain has an important role in central regulation of metabolism and may also be crucial for proper brain function (12)(13)(14). We have previously demonstrated that mice with insulin resistance in brain due to targeted deletion of the insulin receptor (NIRKO mice) develop hyperphagia, mild obesity, reduced fertility, and decreased counterregulatory response to hypoglycemia (15, 16). NIRKO mice also display glycogen synthase kinase 3 beta (GSK3-beta) activation, resulting in hyperphosphorylation of tau protein, a hallmark of e...

MicroRNAs (miRNAs) have within the past decade emerged as key regulators of metabolic homoeostasis. Major tissues in intermediary metabolism important during development of the metabolic syndrome, such as β‐cells, liver, skeletal and heart muscle as well as adipose tissue, have all been shown to be affected by miRNAs. In the pancreatic β‐cell, a number of miRNAs are important in maintaining the balance between differentiation and proliferation (miR‐200 and miR‐29 families) and insulin exocytosis in the differentiated state is controlled by miR‐7, miR‐375 and miR‐335. MiR‐33a and MiR‐33b play crucial roles in cholesterol and lipid metabolism, whereas miR‐103 and miR‐107 regulates hepatic insulin sensitivity. In muscle tissue, a defined number of miRNAs (miR‐1, miR‐133, miR‐206) control myofibre type switch and induce myogenic differentiation programmes. Similarly, in adipose tissue, a defined number of miRNAs control white to brown adipocyte conversion or differentiation (miR‐365, miR‐133, miR‐455). The discovery of circulating miRNAs in exosomes emphasizes their importance as both endocrine signalling molecules and potentially disease markers. Their dysregulation in metabolic diseases, such as obesity, type 2 diabetes and atherosclerosis stresses their potential as therapeutic targets. This review emphasizes current ideas and controversies within miRNA research in metabolism.