Reviews & Analysis

Abdominal obesity is associated with an increased risk of cardiovascular disease, insulin resistance, type 2 diabetes mellitus and all-cause mortality, whereas gluteofemoral obesity has opposing associations. In this Review Fredrik Karpe and Katherine Pinnick discuss the developmental and functional differences between upper-body and lower-body fat depots and provide mechanistic insight into the disease-protective effects of lower-body fat.

In this Review, the authors discuss the clinical features of patients with sporadic pituitary adenomas that are associated withAIP or MEN1mutations, and discuss the molecular mechanisms potentially involved in pituitary adenoma tumorigenesis. They also discuss genetic screening of patients with sporadic pituitary adenomas and investigations of relatives of these patients who also have the same genetic mutations.

Collectively known as the thyroid transcription factors (TTFs), expression of NKX2-1, FOXE1, PAX8 and HHEX is essential for normal development and maintenance of the adult thyroid gland. In this Review, the authors discuss the roles of each of TTFs in the developing and adult thyroid gland, as well as in non-thyroid tissues. Mutations in the genes encoding TTFs can result in a spectrum of phenotypes, such as thyroid dysgenesis and thyroid cancer, which are also addressed.

Availability of longitudinal data on the evolution of thyroid nodules and how this progression is influenced by changes in iodine intake is limited. A systematic 11-year follow-up study in Danish adults offers new insights into the relationships between thyroid nodularity, age and iodine intake.

Shortening of leukocyte telomeres is considered a molecular marker for ageing and is suggested to be linked with increased risk of cardiovascular and metabolic disease. A large population-based study with 6 years of follow-up by Révész and colleagues reveals that short telomeres, at both baseline and during follow-up, are associated with an increased risk of metabolic abnormalities.

In this Review, the authors explore the interactions between obesity, haematopoiesis and the immune system through systemic effects and changes to the primary haematopoietic environment—the bone marrow niche. They also discuss the effects of adipocytes and adiposity on haematopoietic stem cell and progenitor cell populations, with the goal of understanding how obesity might compromise the core haematopoietic system.

Despite the availability of a wide range of different dietary strategies for weight loss, unhealthy weight gain and obesity are growing problems. This Review discusses the efficacy of changes in dietary macronutrient content for healthy weight loss and weight management. The underlying causes of interindividual variations in response to the same dietary approach are also discussed and the feasibility and potential implications of personalized weight loss strategies is considered.

Branched-chain amino acid (BCAA) levels are increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance. In this Review, Christopher Lynch and Sean Adams discuss whether and how impaired BCAA metabolism might occur in obesity and how perturbations in BCAA levels reflect the insulin resistant and type 2 diabetes mellitus pathophenotypes.

Stem cells have an important role in the embryogenesis and homeostasis of the adrenal gland. Walczak and Hammer discuss the molecular networks that regulate the establishment and maintenance of the stem cell population in the fetal and definitive adrenal glands and how genetic defects that perturb these pathways contribute to the development of adrenal disease.

Hypoglycaemia is a frequent adverse effect of some therapies for diabetes mellitus, and can have serious consequences. This Review describes the epidemiology of hypoglycaemia in adults with diabetes mellitus, principally in those treated with insulin. The consequences of hypoglycaemia are discussed, with particular focus on the cardiovascular and neurological morbidities that can occur.

A large-scale study with 5.24 million participants has found statistically significant associations between increased BMI and 17 of 22 frequent cancers. The strongest associations were observed for cancers of the endometrium, kidney, gallbladder and uterus. Questions remain as to whether several of the weaker associations reported in this study reflect genuinely causal relationships.

The prevalence of obesity has increased to epidemic proportions. In the past few years, whether patients with obesity can be metabolically healthy has been debated. This Review discusses the controversy regarding metabolically healthy obesity, as well as the debate regarding the relative importance of fatness versus fitness for overall, and particularly cardiovascular, health.

Determination, differentiation and development of the gonads are important processes in early mammalian development. This article is focused on the genetic networks underlying these processes, whose disruption in humans can lead to disorders of sex development. The authors discuss the pathways controlling sex-specific gonadal development, from the bipotential gonad to the fully differentiated ovary or testis.

The prevalence of type 2 diabetes mellitus (T2DM) is increasing in young Asian adults; however, little is known about the associated clinical characteristics and the prevalence of complications. A recent Asia-wide prospective cohort study has revealed poor metabolic control in patients with young-onset T2DM, indicating more efficient health-care strategies are warranted to manage this vulnerable population.

Mitochondria have a fundamental role in regulating metabolic pathways and in maintaining energy balance. In this Review, Carole Nasrallah and Tamas Horvath discuss the contribution of mitochondrial function, in particular mitochondrial dynamics, to central metabolism from the hypothalamic perspective and describe how mitochondrial dysfunction can lead to the development of metabolic diseases.

The recently published HPS2–THRIVE study has shown that the addition of extended release niacin to statin therapy in patients with well-controlled levels of LDL cholesterol does not reduce the risk of cardiovascular events and might even increase harm. Consequently, the use of niacin to increase levels of HDL cholesterol is not recommended.

Polycystic ovary syndrome (PCOS) is associated with anovulatory infertility. Many clinicians focus on the use of assisted reproductive technologies other than medical induction of ovulation. A new study demonstrating that the aromatase inhibitor letrozole is superior to clomiphene citrate (the current first-line therapy) for ovulation induction in women with PCOS returns attention to this area.

Although important risk factors for coronary heart disease (CHD) are well known, advances in research might facilitate improved risk stratification of patients. This Review discusses the latest developments in metabolic biomarkers of cardiovascular disease, including lipoproteins, homocysteine, calcium metabolism and glycaemic markers. It also discusses whether these biomarkers' associations with CHD are sufficient to improve current risk-stratification metrics.

Vitamin D administration lowers blood pressure in animal models, but findings from studies in humans are inconsistent. Vimaleswaran and colleagues used a Mendelian randomization approach to show that alleles associated with increased plasma levels of 25-hydroxyvitamin D₃ are associated with a reduced risk of hypertension, suggesting a causal relationship in humans.

Of late, clinical trial data, meta-analyses and observational studies have caused concern that the use of calcium supplements might increase the risk of myocardial infarction and stroke. A new meta-analysis suggests that there is no problem with calcium supplements, but as the analysis includes controversial data omitted from previous analyses, the debate will continue.