Brown Adipose Tissue: A Short Historical Perspective.

Brown adipose tissue (BAT) was first identified by Conrad Gessner in 1551, but it was only in 1961 that it was firmly identified as a thermogenic organ. Key developments in the subsequent two decades demonstrated that: (1) BAT is quantitatively important to non-shivering thermogenesis in rodents, (2) uncoupling of oxidative phosphorylation through a mitochondrial proton conductance pathway is the central mechanism by which heat is generated, (3) uncoupling protein-1 is the critical factor regulating proton leakage in BAT mitochondria. Following pivotal studies on cafeteria-fed rats and obese ob/ob mice, BAT was then shown to have a central role in the regulation of energy balance and the etiology of obesity.

Adipokines: inflammation and the pleiotropic role of white adipose tissue.

I had been working on the endocrine and signalling role of white adipose tissue (WAT) since 1994 following the identification of the ob (Lep) gene(1), this after some 15 years investigating the physiological role of brown adipose tissue. The ob gene, a mutation in which it is responsible for the profound obesity of ob/ob (Lepob/Lepob) mice, is expressed primarily in white adipocytes and encodes the pleiotropic hormone leptin. The discovery of this adipocyte hormone had wide-ranging implications, including that white fat has multiple functions that far transcend the traditional picture of a simple lipid storage organ.

Oxygen in Metabolic Dysfunction and Its Therapeutic Relevance.

In recent years, a number of studies have shown altered oxygen partial pressure at a tissue level in metabolic disorders, and some researchers have considered oxygen to be a (macro) nutrient. Oxygen availability may be compromised in obesity and several other metabolism-related pathological conditions, including sleep apnea-hypopnea syndrome, the metabolic syndrome (which is a set of conditions), type 2 diabetes, cardiovascular disease, and cancer. Strategies designed to reduce adiposity and its accompanying disorders have been mainly centered on nutritional interventions and physical activity programs.

Is energy expenditure reduced in obese mice with mutations in the leptin/leptin receptor genes?

Rodents with mutations in the leptin, or leptin receptor, genes have been extensively used to investigate the regulation of energy balance and the factors that underlie the development of obesity. The excess energy gain of these mutants has long been considered as being due in part to increased metabolic efficiency, consequent to reduced energy expenditure, but this view has recently been challenged. We argue, particularly though not exclusively, from data on / mice, that three lines of evidence support the proposition that reduced expenditure is important in the aetiology of obesity in leptin pathway mutants (irrespective of the genetic background): (i) milk intake is similar in suckling / and / mice; (ii) / mice deposit excess energy when pair-fed to the food intake of lean siblings; (iii) in several studies mutant mice have been shown to exhibit a lower RMR 'per animal' at temperatures below thermoneutrality.

Through fat and thin - a journey with the adipose tissues.

The paper is based on the lecture that I gave on receiving the Nutrition Society's inaugural Gowland Hopkins Award for contributions to Cellular and Molecular Nutrition. It reviews studies on the adipose tissues, brown and white, conducted by the groups that I have led since entering nutrition research in 1975. The initial focus was on exploring metabolic factors that underpin the development of obesity using animal models.

Oxygen-A Critical, but Overlooked, Nutrient.

Gaseous oxygen is essential for all aerobic animals, without which mitochondrial respiration and oxidative phosphorylation cannot take place. It is not, however, regarded as a "nutrient" by nutritionists and does not feature as such within the discipline of nutritional science. This is primarily a consequence of the route by which O enters the body, which is via the nose and lungs in terrestrial animals as opposed to the mouth and gastrointestinal tract for what are customarily considered as nutrients.

IL-33 stimulates expression of the GPR84 (EX33) fatty acid receptor gene and of cytokine and chemokine genes in human adipocytes.

Expression of GPCR fatty acid sensor/receptor genes in adipocytes is modulated by inflammatory mediators, particularly IL-1β. In this study we examined whether the IL-1 gene superfamily member, IL-33, also regulates expression of the fatty acid receptor genes in adipocytes. Human fat cells, differentiated from preadipocytes, were incubated with IL-33 at three different dose levels for 3 or 24 h and mRNA measured by qPCR.

Oxygen - the forgotten nutrient.

O is essential for the maintenance and growth of aerobic animals, similar to the essentiality of what are classically considered nutrients. Nevertheless, O is not customarily regarded as a nutrient, this reflecting the route by which it enters the body - through the lungs or gills in vertebrates, rather than via the mouth and gastrointestinal tract. A relative deficiency of O occurs at high altitudes and during deep-sea diving, to which distinct adaptations occur.

IL-1β and TNFα inhibit GPR120 (FFAR4) and stimulate GPR84 (EX33) and GPR41 (FFAR3) fatty acid receptor expression in human adipocytes: implications for the anti-inflammatory action of n-3 fatty acids.

Regulation of the expression of GPCR fatty acid receptor genes has been examined in human adipocytes differentiated in culture. TNFα and IL-1β induced a marked reduction in GPR120 expression, mRNA level falling 17-fold at 24 h in adipocytes incubated with TNFα. In contrast, GPR84 mRNA was dramatically increased by these cytokines (>500-fold for IL-1β at 4 h); GPR41 expression was also stimulated.

PCR arrays indicate that the expression of extracellular matrix and cell adhesion genes in human adipocytes is regulated by IL-1β (interleukin-1β).

The role of IL-1β in regulating the expression of extracellular matrix (ECM) and cell adhesion genes in human adipocytes has been examined. Adipocytes differentiated in culture were incubated with IL-1β for 4 or 24 h and RNA probed with PCR arrays for 84 ECM and cell adhesion genes. Treatment with IL-1β resulted in changes in the expression at one or both time points of ∼50% of the genes probed by the arrays, the majority being down-regulated.

Origins and early development of the concept that brown adipose tissue thermogenesis is linked to energy balance and obesity.

Brown adipose tissue (BAT) was identified as a thermogenic organ in 1961, and in 1978 shown to be the major site of thermoregulatory non-shivering thermogenesis in rats acclimated to the cold. Investigations in the mid-late 1970s established the uncoupling of oxidative phosphorylation through a proton conductance pathway across the mitochondrial inner membrane as the mechanism for heat production in BAT, this being regulated by UCP1 which was first discovered as a 32,000 M cold-inducible protein. These developments came when those concerned with nutritional energetics were proposing that thermogenesis is a significant factor in energy balance and the aetiology of obesity.

Circulating Levels of the Adipokines Monocyte Chemotactic Protein-4 (MCP-4), Macrophage Inflammatory Protein-1β (MIP-1β), and Eotaxin-3 in Severe Obesity and Following Bariatric Surgery.

The aim of the study was to investigate the involvement of the adipokines eotaxin-3, MIP-1β, and MCP-4 in obesity and related comorbidities and the modification of their circulating levels after bariatric surgery. Eighty severely obese subjects and 20 normal-weight controls were included in the study. Circulating levels of MCP-4, MIP-1β, and eotaxin-3, and the main clinical, biochemical, and instrumental parameters for the evaluation of cardiovascular and metabolic profile were determined in controls and in obese subjects at baseline and 10 months after surgery.

IL-1β (interleukin-1β) stimulates the production and release of multiple cytokines and chemokines by human preadipocytes.

The effect of IL-1β on cytokine and chemokine production by human preadipocytes has been examined. Preadipocytes were incubated with IL-1β, and cytokine and chemokine release was measured at 24 h by protein arrays, while the expression of cytokine/chemokine genes was assessed by qPCR at 4 and 24 h. IL-1β stimulated the secretion of multiple cytokines/chemokines, including IL-6, IL-8, IL-10, IL-13, MCP-4, TNFα and IP-10.

New Physiological Aspects of Brown Adipose Tissue.

Brown adipose tissue is specialised for the generation of heat by non-shivering mechanisms. In rodents, the tissue plays a role in energy balance and the development of obesity, as well as in thermoregulation. Studies using fluorodeoxyglucose positron emission tomography (FDG-PET), together with the identification of uncoupling protein-1, have provided definitive evidence that brown adipose tissue is present in adult humans.

Lipopolysaccharide induces a downregulation of adiponectin receptors in-vitro and in-vivo.

Background. Adipose tissue contributes to the inflammatory response through production of cytokines, recruitment of macrophages and modulation of the adiponectin system. Previous studies have identified a down-regulation of adiponectin in pathologies characterised by acute (sepsis and endotoxaemia) and chronic inflammation (obesity and type-II diabetes mellitus).

PCR array and protein array studies demonstrate that IL-1β (interleukin-1β) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes.

The role of IL-1β in regulating the expression and secretion of cytokines and chemokines by human adipocytes was examined. Adipocytes were incubated with human IL-1β for 4 or 24 h. The expression of a panel of 84 cytokine/chemokine genes was probed using PCR arrays.