The field of adipose tissue biology has been expanding at a very rapid pace in Nutrition and Health Adipose Tissue and Adipokines in Health and Disease.
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- Obesity Hormones in Health and Disease
- Adipose Tissue and Adipokines in Health and Disease
- Regulation of energy balance
Adipose tissue is made up of adipocytes, white blood cells, and fibroblasts, surrounded by connective tissue, collagen, nerves and blood vessels. Adipose cells constitute the majority of adipose tissue volume. In this tissue sample, adipocytes are easily recognized by the large lipid droplets. Previously, it was believed that we are born with a certain amount of adipocytes and that the production of new cells ceased early in life.
However, although the number of fat cells appears to stay relatively constant throughout life even after marked weight loss , indicating that the number of adipocytes is set during childhood and adolescence, the adipocyte number is continuously determined by the balance between the production of new cells and the removal of older cells.
Hypertrophy may lead to adipocyte dysfunction that may provoke abnormal endocrine and immune responses and eventually lead to the metabolic abnormalities typical of sick fat. In obesity, adipocyte hypertrophy and inflammatory responses are closely associated with the development of insulin resistance in adipose tissue. Recent data shows that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation In obesity, adipose tissue exhibits a major inflammatory response with increased production of inflammation-related proteins called adipokines.
It has been proposed that hypoxia may underlie this inflammatory response and evidence that adipose tissue is hypoxic in obesity has been obtained in animal models Triglycerides are composed of three molecules of fatty acids attached to a glycerol molecule. If adipocytes are unable to store energy, free fatty acids may enter the blood stream spill-over which may have harmful effects on non-adipose tissue, affecting organs such as the liver, kidneys, pancreas, peripheral muscle, heart, and blood vessels.
This phenomenon is termed lipotoxicity Lipotoxicity may play a role in the development of non-alcoholic fatty liver disease They are produced by a broad range of cells and appear to play a major role for the human body. They also modulate immune functions and inflammatory processes. Adipokines may affect other cells around them as well as remote organs such as the liver, heart, blood vessels, and peripheral muscle.
Although they play a major role in normal bodily processes, they may also participate in various pathological situations, including obesity, type 2 diabetes, and cardiovascular disease.
Adipokines are peptides produced by adipocytes. They mediate communication between adipose tissue and other tissues and organs. Dysregulation of adipokine secretion is present in adiposopathy and promotes inflammatory responses, insulin resistance, type 2 diabetes, heart disease and fatty liver disease. Adipokines in connective tissue diseases Review; Authors: Karolina Sawicka, Dorota Krasowska clinexprheumatol. Currently, there are more than known adipokines Some adipokines may negatively affect health. Leptin is a amino acid hormone synthesized by adipocytes.
Leptin production correlates with of the amount of adipose tissue in the body.
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Obese people, therefore, produce more leptin than people with normal body weight. Leptin receptors are found on a wide range of other cell types. Leptin regulates energy intake and feeding behavior through receptors within the brain particularly in the hypothalamus by providing feedback information about the status of energy reserves.
In other words, adipose tissue uses leptin to communicate with the hypothalamus.
The signals can be twofold. It is the role of the hypothalamus to respond adequately to these signals. Thus, obese individuals show resistance to leptin, similar to insulin resistance in type 2 diabetes.
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It is believed that normal adipokine production and secretion becomes affected when adipose tissue becomes sick. Sick fat shows signs of dysregulated production of adipokines. Increased production of IL-6, TNF-alfa and reduced production of adiponectin may promote inflammation and insulin resistance Hence, abnormal or inappropriate secretion of adipokines may be an important link between sick fat and the metabolic abnormalities associated with obesity, type 2 diabetes, and cardiovascular disease. Although body mass index is often used to define obesity, obesity as a disease is not primarily a weight issue.
The enzyme lipoprotein lipase is released from adipocytes for the breakdown of circulating triacylglycerols to fatty acids, which are subsequently stored within fat cells. In the late s, a further secreted protein from adipocytes was identified, namely, adipsin, a complement-related factor 23 , Adipsin was initially thought to be a direct signal in energy balance, but this was subsequently found not to be the case.
The pivotal change in perspective on the role of WAT as a secretory organ came with the identification of the hormone leptin in Leptin, a 16, MW cytokine-like protein, is a critical hormonal signal from adipocytes in the regulation of appetite and energy balance 21 , 31 , 32 , interacting with several hypothalamic orexigenic and anorexigenic pathways. Thus, the neuropeptide Y, melanin-concentrating hormone, orexin A, agouti-related peptide, and cannabinoid systems have each been reported to be inhibited by leptin 33 — These multiple effects of leptin result in a powerful suppression of food intake.
However, the rate of energy deposition of the obese was 3 times that of the lean The identification of leptin led to the recognition that white fat is an important endocrine organ. Indeed, it is now evident that white adipocytes secrete a multiplicity of protein signals and factors Fig. The diversity of the adipokines is considerable, in terms of both protein structure and function.
The adipokines encompass classical cytokines e. Major adipokines secreted from white adipose tissue.
Obesity Hormones in Health and Disease
The figure shows some of the key adipokines, particularly those linked to inflammation. From the wide range of adipokines identified over the past few years, it is apparent that white fat is a secretory organ of considerable complexity that is closely integrated into overall physiological and metabolic control 15 , 16 , 21 , A corollary to the secretion of such a wide range of protein signals and factors is that WAT communicates extensively with other organs. Co-culture studies indicated, for example, that adipocytes signal directly to other tissues such as the adrenal cortex 42 , and there is a distinct cross-talk between white adipocytes and the brain through leptin and the sympathetic nervous system Indeed, the sympathetic system plays an important role in the regulation of leptin production in white adipocytes 32 , whereas leptin stimulates the sympathetic activity in several organs, including the kidneys and brown adipose tissue A number of adipokines are linked to inflammation and the immune response Fig.
Indeed, preadipocytes are reported to be able to act like macrophages 44 , The inflammation-related adipokines include cytokines, chemokines, and acute phase proteins 15 , 16 , Clear evidence for the expression and secretion of the following cytokines and chemokines has been documented: Acute phase proteins that have been clearly identified as adipokines are haptoglobin, serum amyloid-A, and plasminogen activator inhibitor-1 PAI PAI-1 is also, of course, a key agent in vascular hemostasis In addition to these factors, several other inflammation-related adipokines are recognized, including leptin, the angiogenic protein VEGF, and the first of the family of neurotrophins to be discovered, namely, nerve growth factor NGF 16 , 48 , Importantly, the major adipocyte hormone adiponectin has an anti-inflammatory action 50 in addition to its role in insulin sensitivity and several other metabolic processes 51 , There is, however, an important exception to this general pattern of increased production; the expression and circulating levels of adiponectin decline in obesity Inflammation in WAT is now thought to be powerfully augmented in obesity through the infiltration of macrophages as tissue mass expands 18 , Inflammation is one of the most important developing areas in obesity biology; the obese state was recognized recently as characterized by chronic low-grade inflammation 54 — The main basis for this view is that the circulating levels of several markers of inflammation, such as IL-6, IL, C-reactive protein, PAI-1, and haptoglobin, are elevated in obesity and are reduced with weight loss 54 , 56 , 58 , Given that WAT secretes a wide range of inflammation-related adipokines, it is probable that the tissue is the source of at least some of the elevated plasma levels of these factors in the obese.
It is increasingly thought that the mild inflammatory state of obesity, and particularly the production of inflammatory adipokines, is important in the development of the diseases associated with a high BMI In particular, insulin resistance, type 2 diabetes, and atherosclerosis, as well as other components of the metabolic syndrome, were causally linked to inflammation.
This parallels the growing recognition of the importance of inflammation as an element in a wide range of diseases, including those associated with aging such as the dementias However, much work must be done to unravel the mechanistic basis for the link between specific inflammatory adipokines and the metabolic syndrome.
The reason why obesity should be accompanied by inflammation has received little attention. We recently argued the parsimonious view that given the increased production of inflammation-related adipokines in WAT, the tissue is the main site of direct inflammation in obesity, and raised circulating levels of inflammatory markers reflect spillover from fat rather than serve as an indication of systemic inflammation We argued further that this occurs as a response to hypoxia, proposing that as WAT mass expands in obesity, pockets of adipocytes distant from the vasculature become relatively low in oxygen Hypoxia then leads to the stimulation of the production and release of inflammatory cytokines, chemokines, and angiogenic factors to stimulate blood flow and increase vascularization This general proposal has parallels with the metabolic responses in wound healing and to the events within solid tumors 62 , and involves the recruitment of the transcription factor hypoxia inducible factor-1, which is regarded as the molecular sensor of low oxygen tension 63 , The continuing increase in the incidence of obesity and its associated disorders in affluent populations will provide an ongoing focus for investigation of the fundamental mechanisms of energy regulation.
White adipocytes are key endocrine and secretory cells that release a wide range of regulatory factors. There is extensive cross-talk between white adipocytes and other cells and tissues through both endocrine and paracrine signaling. The local communication between adipocytes and macrophages within WAT is critical in the inflammatory response exhibited in the tissue in obesity, and perhaps other situations in which body fat increases, particularly because of the link between inflammation and the metabolic syndrome. The cross-talk within WAT is likely to include preadipocytes as well as macrophages and mature adipocytes, and this will be central to the local regulation of adipogenesis.
The endocrine link between WAT and the hypothalamus through leptin is a critical component of the regulation of appetite and energy balance.
Adipose Tissue and Adipokines in Health and Disease
There has been much interest in whether other adipokines also act centrally as signals in energy balance, with possible candidates including IL However, there is recent evidence that adiponectin, a major adipocyte-derived hormone, plays a direct role in the regulation of energy balance. This pleiotropic adipokine reduces body weight and, intriguingly, appears to do so without affecting appetite, the central action involving stimulation of energy expenditure The effect on expenditure may occur through the melanocortin system and involve, at least in part, an activation of brown adipose tissue thermogenesis Given the public health concern with obesity, most studies have inevitably focused directly on humans or laboratory rodents as models.
Many of the concepts that have been established in these species are likely, however, to be applicable to companion animals. With a view to exploring the link between inflammation and obesity-associated diseases in dogs, we recently began exploring the extent to which canine adipose tissue synthesizes inflammatory adipokines.
Regulation of energy balance
Furthermore, expression takes place in the adipocytes themselves, as demonstrated through fractionation of freshly isolated tissue and after differentiation of fibroblastic preadipocytes into mature adipocytes in primary culture Thus, canine WAT appears similar to the human and rodent tissue in its ability to produce major inflammatory adipokines. The similarities between the metabolic syndrome in dogs and humans 67 , together with the availability of the canine genome sequence 68 , suggest that rapid progress can be made in exploring the links among WAT, adipokines, inflammation, and metabolic disease in companion animals.
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Abstract There has been a rapid rise in the incidence of obesity, primarily as a result of changes in lifestyle diet and activity levels. View large Download slide.