Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue i...

Brown Adipose Tissue: Function and Physiological Significance

The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes

Biology of Incretins: GLP-1 and GIP

The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism

There has been much effort recently to define the role of adipocytokines, which are soluble mediators derived mainly from adipocytes (fat cells), in the interaction between adipose tissue, inflammation and immunity. The adipocytokines adiponectin and leptin have emerged as the most abundant adipocyte products, thereby redefining adipose tissue as a key component not only of the endocrine system, but also of the immune system. Indeed, as we discuss here, several adipocytokines have a central role in the regulation of insulin resistance, as well as many aspects of inflammation and immunity. Other adipocytokines, such as visfatin, have only recently been identified. Understanding this rapidly growing family of mainly adipocyte-derived mediators might be of importance in the development of new therapies for obesity-associated diseases.

Adipocytokines: mediators linking adipose tissue, inflammation and immunity.

Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus(1). The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons(2) in the arcuate nucleus, which is accessible to peripheral hormones(3). Peptide YY3-36 (PYY3-36), a Y2R agonist(4), is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal(5-7). Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons(8). In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.

Gut hormone PYY 3-36 physiologically inhibits food intake

Background: The gut hormone fragment peptide YY3-36 (PYY) reduces appetite and food intake when infused into subjects of normal weight. In common with the adipocyte hormone leptin, PYY reduces food intake by modulating appetite circuits in the hypothalamus. However, in obesity there is a marked resistance to the action of leptin, which greatly limits its therapeutic effectiveness. We investigated whether obese subjects were also resistant to the anorectic effects of PYY.Methods: We compared the effects of PYY infusion on appetite and food intake in 12 obese and 12 lean subjects in a double-blind, placebo-controlled, crossover study. The plasma levels of PYY, ghrelin, leptin, and insulin were also determined.Results: Caloric intake during a buffet lunch offered two hours after the infusion of PYY was decreased by 30 percent in the obese subjects (P<0.001) and 31 percent in the lean subjects (P<0.001). PYY infusion also caused a significant decrease in the cumulative 24-hour caloric intake in both obese and lean subjects. PYY infusion reduced plasma levels of the appetite-stimulatory hormone ghrelin. Endogenous fasting and postprandial levels of PYY were significantly lower in obese subjects (the mean [+/-SE] fasting PYY levels were 10.2+/-0.7 pmol per liter in the obese group and 16.9+/-0.8 pmol per liter in the lean group, P<0.001). Furthermore, the fasting PYY levels correlated negatively with the body-mass index (r=-0.84, P<0.001).Conclusions: We found that obese subjects were not resistant to the anorectic effects of PYY. Endogenous PYY levels were low in the obese subjects, suggesting that PYY deficiency may contribute to the pathogenesis of obesity.

/pdf/inhibition-of-food-intake-in-obese-subjects-by-peptide-yy3-2m248vmprx.pdf

Inhibition of food intake in obese subjects by peptide YY3-36.

Ghrelin, a circulating growth hormone-releasing peptide derived from the stomach, stimulates food intake. The lowest systemically effective orexigenic dose of ghrelin was investigated and the resulting plasma ghrelin concentration was compared with that during fasting. The lowest dose of ghrelin that produced a significant stimulation of feeding after intraperitoneal injection was 1 nmol. The plasma ghrelin concentration after intraperitoneal injection of 1 nmol of ghrelin (2.83 +/- 0.13 pmol/ml at 60 min postinjection) was not significantly different from that occurring after a 24-h fast (2.79 +/- 0.32 pmol/ml). After microinjection into defined hypothalamic sites, ghrelin (30 pmol) stimulated food intake most markedly in the arcuate nucleus (Arc) (0-1 h food intake, 427 +/- 43% of control; P < 0.001 vs. control, P < 0.01 vs. all other nuclei), which is potentially accessible to the circulation. After chronic systemic or intracerebroventricular (ICV) administration of ghrelin for 7 days, cumulative food intake was increased (intraperitoneal ghrelin 13.6 +/- 3.4 g greater than saline-treated, P < 0.01; ICV ghrelin 19.6 +/- 5.5 g greater than saline-treated, P < 0.05). This was associated with excess weight gain (intraperitoneal ghrelin 21.7 +/- 1.4 g vs. saline 10.6 +/- 1.9 g, P < 0.001; ICV ghrelin 15.3 +/- 4.3 g vs. saline 2.2 +/- 3.8 g, P < 0.05) and adiposity. These data provide evidence that ghrelin is important in long-term control of food intake and body weight and that circulating ghrelin at fasting concentrations may stimulate food intake.

https://diabetes.diabetesjournals.org/content/diabetes/50/11/2540.full.pdf

Ghrelin Causes Hyperphagia and Obesity in Rats

The rising prevalence of obesity in developed societies is causing a major health threat in terms of morbidity and mortality.1 The complications of obesity, especially type 2 diabetes mellitus (T2DM), are placing growing demand on healthcare resources.1,2 Existing medical therapeutic strategies to achieve and maintain clinically significant weight loss remain limited.3 Surgical procedures for the treatment of obesity are, however, highly effective in achieving substantial and sustained weight loss,4,5 but they are technically demanding and costly and carry small but significant rates of morbidity and mortality.6

Dramatic improvements in glycemic control have been observed in subjects with T2DM following bariatric surgery, and specifically the Roux-en-Y gastric bypass (RYGB) procedure.7–11 In the early postoperative period following RYGB, many patients with T2DM discontinue all antidiabetic medication, and may achieve normal fasting plasma glucose concentrations even before substantial weight loss has occurred.10,11 It has been postulated that the improvements in glycemic control, reduction in appetite, and subsequent weight loss following bypass surgery may be due to changes in circulating gut hormones.10,12–14

A number of peptides released from the gastrointestinal tract have recently been shown to regulate appetite and food intake, effecting both orexigenic and anorexic outcomes through actions on the hypothalamic arcuate nucleus.15,16 Ghrelin, a hormone produced from the stomach in the preprandial state, increases expression of the orexigenic hypothalamic neuropeptide Y (NPY) and stimulates food intake in rodents and humans.17,18 In contrast, peptide YY (PYY), released postprandially from the distal gastrointestinal tract, acts within the arcuate nucleus to inhibit the release of NPY19. Intravenous PYY3–36 infusions into humans and intraperitoneal injections into rodents induce satiety and reduce food intake.19,20 Glucagon-like peptide 1 (GLP-1) acts mainly as an incretin, promoting postprandial insulin release21 and improving pancreatic β-cell function,22 and has also been reported to inhibit food intake in humans.23 Pancreatic polypeptide (PP) has recently been shown to inhibit appetite and food intake and promotes energy expenditure.24,25

We sought to determine the changes in the entero-hypothalamic endocrine axis in human subjects following bariatric surgery, examining the meal-stimulated release of PYY, GLP-1, and PP. We used a rodent model of jejuno-intestinal bypass (JIB) surgery to further examine gut hormone changes and to investigate the potential role of PYY in mediating the food intake and weight reducing effects of surgery.

Gut Hormone Profiles Following Bariatric Surgery Favor an Anorectic State, Facilitate Weight Loss, and Improve Metabolic Parameters

Objective:To evaluate the physiologic importance of the satiety gut hormones.Background:Controversy surrounds the physiologic role of gut hormones in the control of appetite. Bariatric surgery remains the most effective treatment option for obesity, and gut hormones are implicated in the reduction o

Mohammad A. Ghatei

Papers

Gut hormone PYY 3-36 physiologically inhibits food intake

Inhibition of food intake in obese subjects by peptide YY3-36.

Ghrelin Causes Hyperphagia and Obesity in Rats

Gut Hormone Profiles Following Bariatric Surgery Favor an Anorectic State, Facilitate Weight Loss, and Improve Metabolic Parameters

Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass.